Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof

ABSTRACT

Indazole compounds for treating various diseases and pathologies are disclosed. More particularly, the present invention concerns the use of an indazole compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer&#39;s disease and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases due to mutations in Wnt signaling components. Also provided are methods for treating Wnt-related disease states.

RELATED APPLICATIONS Cross-Reference to Related Applications

This application is a continuation application of U.S. application Ser.No. 15/184,553, filed Jun. 16, 2016, which is a continuation applicationof U.S. application Ser. No. 14/741,645, filed Jun. 17, 2015, which is acontinuation application of U.S. application Ser. No. 14/334,005, filedJul. 17, 2014, which is a continuation application of U.S. applicationSer. No. 13/552,188, filed Jul. 18, 2012, which is a continuation ofU.S. application Ser. No. 12/852,706, filed Aug. 9, 2010, which claimsthe benefit of U.S. Provisional Application No. 61/232,603, filed Aug.10, 2009 and U.S. Provisional Application No. 61/305,459, filed Feb. 17,2010, all of which are incorporated herein by reference in theirentirety.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to inhibitors of one or more proteins in the Wntpathway, including inhibitors of one or more Wnt proteins, andcompositions comprising the same. More particularly, it concerns the useof an indazole compound or salts or analogs thereof, in the treatment ofdisorders characterized by the activation of Wnt pathway signaling(e.g., cancer, abnormal cellular proliferation, angiogenesis,Alzheimer's disease and osteoarthritis), the modulation of cellularevents mediated by Wnt pathway signaling, as well as genetic diseasesdue to mutations in Wnt signaling components.

Description of the Related Art

Pattern formation is the activity by which embryonic cells form orderedspatial arrangements of differentiated tissues. Speculation on themechanisms underlying these patterning effects usually centers on thesecretion of a signaling molecule that elicits an appropriate responsefrom the tissues being patterned. More recent work aimed at theidentification of such signaling molecules implicates secreted proteinsencoded by individual members of a small number of gene families.

A longstanding idea in cancer biology is that cancers arise and grow dueto the formation of cancer stem cells, which may constitute only aminority of the cells within a tumor but are nevertheless critical forits propagation. Stem cells are appealing as the cell of origin forcancer because of their pre-existing capacity for self-renewal and forunlimited replication. In addition, stem cells are relatively long-livedin comparison to other cells within tissues, providing a greateropportunity to accumulate the multiple additional mutations that may berequired to increase the rate of cell proliferation and produceclinically significant cancers. Of particular recent interest in theorigin of cancer is the observation that the Wnt signaling pathway,which has been implicated in stem cell self-renewal in normal tissues,upon continuous activation has also been associated with the initiationand growth of many types of cancer. This pathway thus provides apotential link between the normal self-renewal of stem cells and theaberrantly regulated proliferation of cancer stem cells.

The Wnt growth factor family includes more than 10 genes identified inthe mouse and at least 7 genes identified in the human. Members of theWnt family of signaling molecules mediate many important short- andlong-range patterning processes during invertebrate and vertebratedevelopment. The Wnt signaling pathway is known for its important rolein the inductive interactions that regulate growth and differentiation,and likely also plays important roles in the homeostatic maintenance ofpost-embryonic tissue integrity. Wnt stabilizes cytoplasmic p-catenin,which stimulates the expression of genes including c-myc, c jun, fra-1,and cyclin Dl. In addition, misregulation of Wnt signaling can causedevelopmental defects and is implicated in the genesis of several humancancers. More recently, the Wnt pathway has been implicated in themaintenance of stem or progenitor cells in a growing list of adulttissues that now includes skin, blood, gut, prostate, muscle and thenervous system.

Pathological activation of the Wnt pathway is also believed to be theinitial event leading to colorectal cancer in over 85% of all sporadiccases in the Western world. Activation of the Wnt pathway has also beenextensively reported for hepatocellular carcinoma, breast cancer,ovarian cancer, pancreatic cancer, melanomas, mesotheliomas, lymphomasand leukemias. In addition to cancer, inhibitors of the Wnt pathway canbe used for stem cell research or for the treatment of any diseasescharacterized by aberrant Wnt activation such as diabetic retinopathy,neovascular glaucoma, rheumatoid arthritis, psoriasis as well as mycoticand viral infections and bone and cartilage diseases. As such, it is atherapeutic target that is of great interest to the field.

In addition to cancer, there are many cases of genetic diseases due tomutations in Wnt signaling components. Examples of some of the manydiseases are Alzheimer's disease [Proc. Natl. Acad. Sci. USA (2007),104(22), 9434-9], osteoarthritis, polyposis coli [Science (1991),253(5020), 665-669], osteoporosis-pseudoglioma syndrome [N. Engl. J.Med. (2002), 346(20), 1513-21], familial exudative vitreoretinopathy[Hum. Mutat. (2005), 26(2), 104-12], retinal angiogenesis [Nat. Genet.(2002), 32(2), 326-30], early coronary disease [Science (2007),315(5816), 1278-82], tetra-amelia syndrome [Am. J. Hum. Genet. (2004),74(3), 558-63], Müllerian-duct regression and virilization [Engl. J.Med. (2004), 351(8), 792-8], SERKAL syndrome [Am. J Hum. Genet. (2008),82(1), 39-47], diabetes mellitus type 2 [Am. J Hum. Genet. (2004),75(5), 832-43; N. Engl. J. Med. (2006), 355(3), 241-50], Fuhrmannsyndrome [Am. J. Hum. Genet. (2006), 79(2), 402-8],Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome [Am. J. Hum.Genet. (2006), 79(2), 402-8], odonto-onycho-dermal dysplasia [Am. J.Hum. Genet. (2007), 81(4), 821-8], obesity [Diabetologia (2006), 49(4),678-84], split-hand/foot malformation [Hum. Mol. Genet. (2008), 17(17),2644-53], caudal duplication syndrome [Am. J. Hum. Genet. (2006), 79(1),155-62], tooth agenesis [Am. J. Hum. Genet. (2004), 74(5), 1043-50],Wilms tumor [Science (2007), 315(5812), 642-5], skeletal dysplasia [Nat.Genet. (2009), 41(1), 95-100], focal dermal hypoplasia [Nat. Genet.(2007), 39(7), 836-8], autosomal recessive anonychia [Nat. Genet.(2006), 38(11), 1245-7], neural tube defects [N. Engl. J. Med. (2007),356(14), 1432-7], alpha-thalassemia (ATRX) syndrome [The Journal ofNeuroscience (2008), 28(47), 12570-12580], fragile X syndrome [PLoSGenetics (2010), 6(4), e1000898], ICF syndrome, Angelman syndrome [BrainResearch Bulletin (2002), 57(1), 109-119], Prader-Willi syndrome[Journal of Neuroscience (2006), 26(20), 5383-5392], Beckwith-WiedemannSyndrome [Pediatric and Developmental Pathology (2003), 6(4), 299-306]and Rett syndrome.

SUMMARY OF THE INVENTION

The present invention makes available methods and reagents, involvingcontacting a cell with an agent, such as an aromatic compound, in asufficient amount to antagonize a Wnt activity, e. g., to reverse orcontrol an aberrant growth state or correct an genetic disorder due tomutations in Wnt signaling components.

Some embodiments disclosed herein include Wnt inhibitors containing anindazole core. Other embodiments disclosed herein include pharmaceuticalcompositions and methods of treatment using these compounds.

One embodiment disclosed herein includes a compound having the structureof formula I:

as well as prodrugs and pharmaceutically acceptable salts thereof.

In some embodiments of formula (I):

R¹, R², R⁴, R⁶, R⁷, R⁸ and R⁹ are independently selected from the groupconsisting of H, C₁₋₉ alkyl, halide, —CF₃, —(C₁₋₉alkyl)_(n)carbocyclylR¹³, —(C₁₋₉ alkyl)_(n)heterocyclylR¹³, —(C₁₋₉alkyl)_(n)arylR¹³, —(C₁₋₉ alkyl)_(n)heteroarylR¹³, —(C₁₋₉alkyl)_(n)OR¹⁰, —(C₁₋₉ alkyl)_(n)SR¹⁰, —(C₁₋₉ alkyl)_(n)S(═O)R¹¹, —(C₁₋₉alkyl)_(n)SO₂R¹⁰, —(C₁₋₉ alkyl)_(n)N(R¹⁰)SO₂R¹⁰, —(C₁₋₉alkyl)_(n)SO₂N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)C(=A)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)NR¹⁰C(═O)OR¹⁰, —(C₁₋₉alkyl)_(n)C(=A)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)C(=A)R¹⁰, —(C₁₋₉alkyl)_(n)OC(═O)N(R¹⁰)₂, —NO₂, —CN, —(C₁₋₉ alkyl)_(n)CO₂R¹⁰ and —(C₁₋₉alkyl)_(n)C(=A)R¹⁰;

R³ is selected from the group consisting of —NRS(═O)R¹⁴,—(C₁₋₉alkyl)R¹⁴, -carbocyclylR¹⁴R¹⁵, -heterocyclylR¹⁴R¹⁵, -arylR¹⁴R¹⁵ or-heteroarylR¹⁴R¹⁵;

alternatively, one of each R¹ and R², R² and R³, R³ and R⁴, R⁶ and R⁷,R⁷ and R⁸ or R⁸ and R⁹ are taken together to form a ring which isselected from the group consisting of aryl, heteroaryl,

wherein each bond represented by a dashed and solid line represents abond selected from the group consisting of a single bond and a doublebond;

each R¹⁰ is independently selected from the group consisting of H, —C₁₋₉alkyl, —CF₃, —(C₁₋₉ alkyl)_(n)carbocyclyl, —(C₁₋₉alkyl)_(n)heterocyclyl, —(C₁₋₉ alkyl)_(n)aryl and —(C₁₋₉alkyl)_(n)heteroaryl;

each R¹¹ is independently selected from the group consisting of —C₁₋₉alkyl, —CF₃, —(C₁₋₉ alkyl)_(n)carbocyclyl, —(C₁₋₉alkyl)_(n)heterocyclyl, —(C₁₋₉ alkyl)_(n)aryl and —(C₁₋₉alkyl)_(n)heteroaryl;

each R¹² is independently selected from the group consisting of CN,—OR¹⁰ and R¹⁰;

R¹³ is 1-5 substituents each selected from the group consisting of H,C₁₋₉ alkyl, halide, —CF₃, carbocyclylR¹³, heterocyclylR¹³, arylR¹³,heteroarylR¹³, —(C₁₋₉ alkyl)_(n)OR¹⁰, —(C₁₋₉ alkyl)_(n)SR¹⁰, —(C₁₋₉alkyl)_(n)S(═O)R¹¹, —(C₁₋₉ alkyl)_(n)SO₂R¹⁰, —(C₁₋₉alkyl)_(n)N(R¹⁰)SO₂R¹⁰, —(C₁₋₉ alkyl)_(n)SO₂N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)C(=A)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)NR¹⁰C(═O)OR¹⁰, —(C₁₋₉ alkyl)_(n)C(=A)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)C(=A)R¹⁰, —(C₁₋₉ alkyl)_(n)OC(═O)N(R¹⁰)₂, —NO₂, —CN,—(C₁₋₉ alkyl)_(n)CO₂R¹⁰ and —(C₁₋₉ alkyl)_(n)C(=A)R¹⁰;

R¹⁴ is selected from the group consisting of —NR¹⁰C(=A)R, —NR¹⁰S(═O)R¹¹,—NR¹⁰SO₂R¹⁰, —NR¹⁰C(═O)N(R¹⁶)₂, —NR¹⁰C(═S)N(R¹⁰)₂, —NR¹⁰C(═NR¹²)N(R¹⁰)₂,—N(R¹⁶)₂, —C(═O)NR¹⁰R¹⁷, —C(═S)N(R¹⁰)₂, —C(═NR¹²)N(R¹⁰)₂, —OC(=A)R¹⁰,—C(=A)R¹⁰, —NR¹⁰C(=A)OR¹⁰ and —OC(=A)NR¹⁰R¹⁰;

R¹⁵ is 1-5 substituents each selected from the group consisting of H,C₁₋₉ alkyl, halide, —CF₃, carbocyclylR¹³, heterocyclylR¹³, arylR¹³,heteroarylR¹³, —(C₁₋₉ alkyl)_(n)OR¹⁰, —(C₁₋₉ alkyl)_(n)SR¹⁰, —(C₁₋₉alkyl)_(n)S(═O)R¹¹, —(C₁₋₉ alkyl)_(n)SO₂R¹⁰, —(C₁₋₉alkyl)_(n)N(R¹⁰)SO₂R¹⁰, —(C₁₋₉ alkyl)_(n)SO₂N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)C(=A)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)NR¹⁰C(═O)OR¹⁰, —(C₁₋₉ alkyl)_(n)C(=A)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)C(=A)R¹⁰, —(C₁₋₉ alkyl)_(n)OC(═O)N(R¹⁰)₂, —NO₂, —CN,—(C₁₋₉ alkyl)_(n)CO₂R¹⁰ and —(C₁₋₉ alkyl)_(n)C(=A)R¹⁰;

R¹⁶ is —C₁₋₉ alkyl;

each R¹⁷ is independently selected from the group consisting of-heterocyclylR¹³, —(C₁₋₉ alkyl)heterocyclylR¹³ and —(C₁₋₉alkyl)carbocyclylR¹³;

R¹⁸ and R¹⁹ are independently selected from the group consisting of H,C₁₋₉ alkyl, halide, —(C₁₋₉ alkyl)_(n)carbocyclylR¹³, —(C₁₋₉alkyl)_(n)heterocyclylR¹³, —(C₁₋₉ alkyl)_(n)arylR¹³, —(C₁₋₉alkyl)_(n)heteroarylR¹³, —(C₁₋₉ alkyl)_(n)OR¹⁰, —(C₁₋₉ alkyl)_(n)SR¹⁰,—(C₁₋₉ alkyl)_(n)S(═O)R¹¹, —(C₁₋₉ alkyl)_(n)SO₂R¹⁰, —(C₁₋₉alkyl)_(n)N(R¹⁰)SO₂R¹⁰, —(C₁₋₉ alkyl)_(n)SO₂N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)C(=A)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)C(=A)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)C(=A)R¹⁰, —NO₂, —CN,—(C₁₋₉ alkyl)_(n)CO₂R¹⁰ and —(C₁₋₉ alkyl)_(n)C(=A)R¹⁰;

alternatively, R¹⁸ and R¹⁹ are taken together to form a ring which isselected from the group consisting of benzene and pyridine;

each A is independently selected from O, S and NR¹²;

X is nitrogen and R⁵ is absent;

Y¹, Y², Y³ and Y⁴ are independently selected from the group consistingof carbon and nitrogen with the proviso that at least one of Y¹, Y², Y³and Y⁴ are nitrogen;

if Y¹ is nitrogen then R⁶ is absent;

if Y² is nitrogen then R⁷ is absent;

if Y³ is nitrogen then R⁸ is absent;

if Y⁴ is nitrogen then R⁹ is absent; and

each n is 0 or 1.

In other embodiments of formula (I):

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are independently selected fromthe group consisting of H, C₁₋₉ alkyl, halide, —CF₃, —(C₁₋₉alkyl)_(n)carbocyclylR¹², —(C₁₋₉ alkyl)_(n)heterocyclylR¹², —(C₁₋₉alkyl)_(n)arylR¹², —(C₁₋₉ alkyl)_(n)heteroarylR¹², —(C₁₋₉ alkyl)_(n)OR⁹,—(C₁₋₉ alkyl)_(n)SR⁹, —(C₁₋₉ alkyl)_(n)S(═O)R¹⁰, —(C₁₋₉ alkyl)_(n)SO₂R⁹,—(C₁₋₉ alkyl)_(n)N(R⁹)S(═O)R¹⁰, —(C₁₋₉ alkyl)_(n)N(R⁹)SO₂R⁹, —(C₁₋₉alkyl)_(n)SO₂N(R⁹)₂, —(C₁₋₉ alkyl)_(n)N(R⁹)₂, —(C₁₋₉alkyl)_(n)N(R⁹)C(=A)N(R⁹)₂, —(C₁₋₉ alkyl)_(n)NR⁹C(═O)OR⁹, —(C₁₋₉alkyl)_(n)C(=A)N(R⁹)₂, —(C₁₋₉ alkyl)_(n)N(R⁹)C(=A)R⁹, —(C₁₋₉alkyl)_(n)OC(═O)NR⁹R⁹, —NO₂, —CN, —(C₁₋₉ alkyl)_(n)CO₂R⁹ and —(C₁₋₉alkyl)_(n)C(=A)R⁹;

alternatively, one of each R¹ and R², R² and R³, R³ and R⁴, R⁶ and R⁷,R⁷ and R⁸ or R⁸ and R⁹ are taken together to form a ring which isselected from the group consisting of aryl, heteroaryl,

wherein each bond represented by a dashed and solid line represents abond selected from the group consisting of a single bond and a doublebond;

each R¹⁰ is independently selected from the group consisting of H, —C₁₋₉alkyl, —CF₃, —(C₁₋₉ alkyl)_(n)carbocyclyl, —(C₁₋₉alkyl)_(n)heterocyclyl, —(C₁₋₉ alkyl)_(n)aryl and —(C₁₋₉alkyl)_(n)heteroaryl;

each R¹¹ is independently selected from the group consisting of —C₁₋₉alkyl, —CF₃, —(C₁₋₉ alkyl)_(n)carbocyclyl, —(C₁₋₉alkyl)_(n)heterocyclyl, —(C₁₋₉ alkyl)_(n)aryl and —(C₁₋₉alkyl)_(n)heteroaryl;

each R¹² is independently selected from the group consisting of CN,—OR¹⁰ and R¹⁰;

R¹³ is 1-5 substituents each selected from the group consisting of H,C₁₋₉ alkyl, halide, —CF₃, carbocyclylR¹², heterocyclylR¹², arylR¹²,heteroarylR¹², —(C₁₋₉ alkyl)_(n)OR⁹, (C₁₋₉ alkyl)_(n)SR⁹, —(C₁₋₉alkyl)_(n)S(═O)R¹⁰, —(C₁₋₉ alkyl)_(n)SO₂R⁹, —(C₁₋₉ alkyl)_(n)N(R⁹)SO₂R⁹,(C₁₋₉ alkyl)_(n)SO₂N(R⁹)₂, —(C₁₋₉ alkyl)_(n)N(R⁹)₂, —(C₁₋₉alkyl)_(n)N(R⁹)C(=A)N(R⁹)₂, —(C₁₋₉ alkyl)_(n)C(=A)N(R⁹)₂, —(C₁₋₉alkyl)_(n)NR⁹C(═O)OR⁹, —(C₁₋₉ alkyl)_(n)N(R⁹)C(=A)R⁹, —(C₁₋₉alkyl)_(n)OC(═O)N(R⁹)₂, —NO₂, —CN, —(C₁₋₉ alkyl)_(n)CO₂R⁹ and —(C₁₋₉alkyl)_(n)C(=A)R⁹;

R¹⁸ and R¹⁹ are independently selected from the group consisting of H,C₁₋₉ alkyl, halide, —(C₁₋₉ alkyl)_(n)carbocyclylR¹³, —(C₁₋₉alkyl)_(n)heterocyclylR¹³, —(C₁₋₉ alkyl)_(n)arylR¹³, —(C₁₋₉alkyl)_(n)heteroarylR¹³, —(C₁₋₉ alkyl)_(n)OR¹⁰, —(C₁₋₉ alkyl)_(n)SR¹⁰,—(C₁₋₉ alkyl)_(n)S(═O)R¹¹, —(C₁₋₉ alkyl)_(n)SO₂R¹⁰, —(C₁₋₉alkyl)_(n)N(R¹⁰)SO₂R¹⁰, —(C₁₋₉ alkyl)_(n)SO₂N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)C(=A)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)C(=A)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)C(=A)R¹⁰, —NO₂, —CN,—(C₁₋₉ alkyl)_(n)CO₂R¹⁰ and —(C₁₋₉ alkyl)_(n)C(=A)R¹⁰;

alternatively, R¹⁸ and R¹⁹ are taken together to form a ring which isselected from the group consisting of benzene and pyridine;

each A is independently selected from O, S and NR¹²;

X is carbon;

Y¹, Y², Y³ and Y⁴ are independently selected from the group consistingof carbon and nitrogen with the proviso that at least one of Y¹, Y², Y³and Y⁴ are nitrogen;

if Y¹ is nitrogen then R⁶ is absent;

if Y² is nitrogen then R⁷ is absent;

if Y³ is nitrogen then R⁸ is absent;

if Y⁴ is nitrogen then R⁹ is absent; and

each n is 0 or 1, or a pharmaceutically acceptable salt or pro-drugthereof.

Some embodiments include stereoisomers and pharmaceutically acceptablesalts of a compound of general formula (I).

Some embodiments include pro-drugs of a compound of general formula (I).

Some embodiments of the present invention include pharmaceuticalcompositions comprising a compound of general formula (I) and apharmaceutically acceptable carrier.

Other embodiments disclosed herein include methods of inhibiting one ormore members of the Wnt pathway, including one or more Wnt proteins byadministering to a subject affected by a disorder or disease in whichaberrant Wnt signaling is implicated, such as cancer and other diseasesassociated with abnormal angiogenesis, cellular proliferation, cellcycling and mutations in Wnt signaling components, a compound accordingto any of the above formulas. Accordingly, the compounds andcompositions provided herein can be used to treat cancer, to reduce orinhibit angiogenesis, to reduce or inhibit cellular proliferation andcorrect an genetic disorder due to mutations in Wnt signalingcomponents. Non-limiting examples of diseases which can be treated withthe compounds and compositions provided herein include a variety ofcancers, diabetic retinopathy, neovascular glaucoma, rheumatoidarthritis, psoriasis, mycotic and viral infections,osteochondrodysplasia, Alzheimer's disease, osteoarthritis, polyposiscoli, osteoporosis-pseudoglioma syndrome, familial exudativevitreoretinopathy, retinal angiogenesis, early coronary disease,tetra-amelia syndrome, Müllerian-duct regression and virilization,SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletaldysplasia, focal dermal hypoplasia, autosomal recessive anonychia,neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile Xsyndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome,Beckwith-Wiedemann Syndrome and Rett syndrome.

Another embodiment disclosed herein includes a pharmaceuticalcomposition that has a compound according to any of the above formulasand a pharmaceutically acceptable carrier, diluent, or excipient.

Some embodiments of the present invention include methods to prepare acompound of general formula (I).

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION OF THE INVENTION

Compositions and methods for inhibiting one or more members of the Wntpathway, including one or more Wnt proteins would be of tremendousbenefit. Certain embodiments provide such compositions and methods.

Some embodiments relate to a method for treating a disease such ascancers, diabetic retinopathy, neovascular glaucoma, rheumatoidarthritis, psoriasis, mycotic and viral infections,osteochondrodysplasia, Alzheimer's disease, osteoarthritis, polyposiscoli, osteoporosis-pseudoglioma syndrome, familial exudativevitreoretinopathy, retinal angiogenesis, early coronary disease,tetra-amelia syndrome, Müllerian-duct regression and virilization,SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletaldysplasia, focal dermal hypoplasia, autosomal recessive anonychia,neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile Xsyndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome,Beckwith-Wiedemann Syndrome and Rett syndrome.

In some embodiments, pharmaceutical compositions are provided that areeffective for treatment of a disease of an animal, e.g., a mammal,caused by the pathological activation or mutations of the Wnt pathway.The composition includes a pharmaceutically acceptable carrier and a Wntpathway inhibitor as described herein.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this disclosure belongs. All patents, applications,published applications, and other publications are incorporated byreference in their entirety. In the event that there is a plurality ofdefinitions for a term herein, those in this section prevail unlessstated otherwise.

In this specification and in the claims, the following terms have themeanings as defined. As used herein, “alkyl” means a branched, orstraight chain chemical group containing only carbon and hydrogen, suchas methyl, isopropyl, isobutyl, sec-butyl and pentyl. Alkyl groups caneither be unsubstituted or substituted with one or more substituents,e.g., halogen, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl,mercapto, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, or otherfunctionality that may be suitably blocked, if necessary for purposes ofthe invention, with a protecting group. Alkyl groups can be saturated orunsaturated (e.g., containing —C═C— or —C≡C— subunits), at one orseveral positions. Typically, alkyl groups will comprise 1 to 9 carbonatoms, preferably 1 to 6, and more preferably 1 to 4 carbon atoms.

As used herein, “carbocyclyl” means a cyclic ring system containing onlycarbon atoms in the ring system backbone, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls mayinclude multiple fused rings. Carbocyclyls may have any degree ofsaturation provided that at least one ring in the ring system is notaromatic. Carbocyclyl groups can either be unsubstituted or substitutedwith one or more substituents, e.g., halogen, alkoxy, acyloxy, amino,amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy,aryl, heteroaryl, or other functionality that may be suitably blocked,if necessary for purposes of the invention, with a protecting group.Typically, carbocyclyl groups will comprise 3 to 10 carbon atoms,preferably 3 to 6.

As used herein, “lower alkyl” means a subset of alkyl, and thus is ahydrocarbon substituent, which is linear, or branched. Preferred loweralkyls are of 1 to about 4 carbons, and may be branched or linear.Examples of lower alkyl include butyl, propyl, isopropyl, ethyl, andmethyl. Likewise, radicals using the terminology “lower” refer toradicals preferably with 1 to about 4 carbons in the alkyl portion ofthe radical.

As used herein, “amido” means a H—CON— or alkyl-CON—, carbocyclyl-CON—,aryl-CON—, heteroaryl-CON— or heterocyclyl-CON group wherein the alkyl,carbocyclyl, aryl or heterocyclyl group is as herein described.

As used herein, “aryl” means an aromatic radical having a single-ring(e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl)with only carbon atoms present in the ring backbone. Aryl groups caneither be unsubstituted or substituted with one or more substituents,e.g., amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro,halo, mercapto, and other substituents. A preferred carbocyclic aryl isphenyl.

As used herein, the term “heteroaryl” means an aromatic radical havingone or more heteroatom(s) (e.g., N, O, or S) in the ring backbone andmay include a single ring (e.g., pyridine) or multiple condensed rings(e.g., quinoline). Heteroaryl groups can either be unsubstituted orsubstituted with one or more substituents, e.g., amino, cyano, hydroxyl,lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto, and othersubstituents. Examples of heteroaryl include thienyl, pyrridyl, furyl,oxazolyl, oxadiazolyl, pyrollyl, imidazolyl, triazolyl, thiodiazolyl,pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazinyl, thiazolyl and others.

In these definitions it is clearly contemplated that substitution on thearyl and heteroaryl rings is within the scope of certain embodiments.Where substitution occurs, the radical is called substituted aryl orsubstituted heteroaryl. Preferably one to three and more preferably oneor two substituents occur on the aryl ring. Though many substituentswill be useful, preferred substituents include those commonly found inaryl compounds, such as alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo,haloalkyl, mercapto and the like.

As used herein, “amide” includes both RNR′CO— (in the case of R=alkyl,alkaminocarbonyl-) and RCONR′— (in the case of R=alkyl, alkylcarbonylamino-).

As used herein, the term “ester” includes both ROCO— (in the case ofR=alkyl, alkoxycarbonyl-) and RCOO— (in the case of R=alkyl,alkylcarbonyloxy-).

As used herein, “acyl” means an H—CO— or alkyl-CO—, carbocyclyl-CO—,aryl-CO—, heteroaryl-CO— or heterocyclyl-CO— group wherein the alkyl,carbocyclyl, aryl or heterocyclyl group is as herein described.Preferred acyls contain a lower alkyl. Exemplary alkyl acyl groupsinclude formyl, acetyl, propanoyl, 2-methylpropanoyl, t-butylacetyl,butanoyl and palmitoyl.

As used herein, “halo or halide” is a chloro, bromo, fluoro or iodo atomradical. Chloro, bromo and fluoro are preferred halides. The term “halo”also contemplates terms sometimes referred to as “halogen”, or “halide”.

As used herein, “haloalkyl” means a hydrocarbon substituent, which islinear or branched or cyclic alkyl, alkenyl or alkynyl substituted withchloro, bromo, fluoro or iodo atom(s). Most preferred of these arefluoroalkyls, wherein one or more of the hydrogen atoms have beensubstituted by fluoro. Preferred haloalkyls are of 1 to about 3 carbonsin length, more preferred haloalkyls are 1 to about 2 carbons, and mostpreferred are 1 carbon in length. The skilled artisan will recognizethen that as used herein, “haloalkylene” means a diradical variant ofhaloalkyl, such diradicals may act as spacers between radicals, otheratoms, or between the parent ring and another functional group.

As used herein, “heterocyclyl” means a cyclic ring system comprising atleast one heteroatom in the ring system backbone. Heterocyclyls mayinclude multiple fused rings. Heterocyclyls may have any degree ofsaturation provided that at least one ring in the ring system is notaromatic. Heterocyclyls may be substituted or unsubstituted with one ormore substituents, e.g., halogen, alkoxy, acyloxy, amino, amido, cyano,nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl,heteroaryl, and other substituents, and are attached to other groups viaany available valence, preferably any available carbon or nitrogen. Morepreferred heterocycles are of 5-7 members. In six membered monocyclicheterocycles, the heteroatom(s) are selected from one up to three of O,N or S, and wherein when the heterocycle is five membered, preferably ithas one or two heteroatoms selected from O, N, or S.

As used herein, “substituted amino” means an amino radical which issubstituted by one or two alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl groups, wherein the alkyl, aryl, heteroaryl or heterocyclylare defined as above.

As used herein, “substituted thiol” means RS— group wherein R is analkyl, an aryl, heteroaryl or a heterocyclyl group, wherein the alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl are defined as above.

As used herein, “sulfonyl” means an alkylSO₂, arylSO₂, heteroarylSO₂,carbocyclylSO₂, or heterocyclyl-SO₂ group wherein the alkyl,carbocyclyl, aryl, heteroaryl or heterocyclyl are defined as above.

As used herein, “sulfamido” means an alkyl-N—S(O)₂N—, aryl-NS(O)₂N—,heteroaryl-NS(O)₂N—, carbocyclyl-NS(O)₂N or heterocyclyl-NS(O)₂N— groupwherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl groupis as herein described.

As used herein, “sulfonamido” means an alkyl-S(O)₂N—, aryl-S(O)₂N—,heteroaryl-S(O)₂N—, carbocyclyl-S(O)₂N— or heterocyclyl-S(O)₂N— groupwherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl groupis as herein described.

As used herein, “ureido” means an alkyl-NCON—, aryl-NCON—,heteroaryl-NCON—, carbocyclyl-NCON— or heterocyclyl-NCON— group whereinthe alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl group is asherein described.

As used herein, when two groups are indicated to be “linked” or “bonded”to form a “ring,” it is to be understood that a bond is formed betweenthe two groups and may involve replacement of a hydrogen atom on one orboth groups with the bond, thereby forming a carbocyclyl, heterocyclyl,aryl, or heteroaryl ring. The skilled artisan will recognize that suchrings can and are readily formed by routine chemical reactions, and itis within the purview of the skilled artisan to both envision such ringsand the methods of their formations. Preferred are rings having from 3-7members, more preferably 5 or 6 members. As used herein the term “ring”or “rings” when formed by the combination of two radicals refers toheterocyclic, carbocyclic, aryl, or heteroaryl rings.

The skilled artisan will recognize that some structures described hereinmay be resonance forms or tautomers of compounds that may be fairlyrepresented by other chemical structures, even when kinetically, theartisan recognizes that such structures are only a very small portion ofa sample of such compound(s). Such compounds are clearly contemplatedwithin the scope of this invention, though such resonance forms ortautomers are not represented herein.

The compounds provided herein may encompass various stereochemicalforms. The compounds also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds. Separation ofthe individual isomers or selective synthesis of the individual isomersis accomplished by application of various methods which are well knownto practitioners in the art. Unless otherwise indicated, when adisclosed compound is named or depicted by a structure withoutspecifying the stereochemistry and has one or more chiral centers, it isunderstood to represent all possible stereoisomers of the compound.

The term “administration” or “administering” refers to a method ofgiving a dosage of a compound or pharmaceutical composition to avertebrate or invertebrate, including a mammal, a bird, a fish, or anamphibian, where the method is, e.g., intrarespiratory, topical, oral,intravenous, intraperitoneal, intramuscular, buccal, rectal, sublingual.The preferred method of administration can vary depending on variousfactors, e.g., the components of the pharmaceutical composition, thesite of the disease, the disease involved, and the severity of thedisease.

A “diagnostic” as used herein is a compound, method, system, or devicethat assists in the identification and characterization of a health ordisease state. The diagnostic can be used in standard assays as is knownin the art.

The term “mammal” is used in its usual biological sense. Thus, itspecifically includes humans, cattle, horses, dogs, and cats, but alsoincludes many other species.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes any and all solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions iscontemplated. Supplementary active ingredients can also be incorporatedinto the compositions. In addition, various adjuvants such as arecommonly used in the art may be included. These and other such compoundsare described in the literature, e.g., in the Merck Index, Merck &Company, Rahway, N.J. Considerations for the inclusion of variouscomponents in pharmaceutical compositions are described, e.g., in Gilmanet al. (Eds.) (2006); Goodman and Gilman's: The Pharmacological Basis ofTherapeutics, 11th Ed., The McGraw-Hill Companies.

The term “pharmaceutically acceptable salt” refers to salts that retainthe biological effectiveness and properties of the compounds of thepreferred embodiments and, which are not biologically or otherwiseundesirable. In many cases, the compounds of the preferred embodimentsare capable of forming acid and/or base salts by virtue of the presenceof amino and/or carboxyl groups or groups similar thereto.Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids. Inorganic acids from which salts canbe derived include, for example, hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acidsfrom which salts can be derived include, for example, acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and thelike. Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases. Inorganic bases from which salts can bederived include, for example, sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum, and thelike; particularly preferred are the ammonium, potassium, sodium,calcium and magnesium salts. Organic bases from which salts can bederived include, for example, primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, basic ion exchange resins, and the like, specificallysuch as isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, and ethanolamine. Many such salts are known in the art,as described in World Patent Publication 87/05297, Johnston et al.,published Sep. 11, 1987 (incorporated by reference herein).

“Solvate” refers to the compound formed by the interaction of a solventand a Wnt pathway inhibitor, a metabolite, or salt thereof. Suitablesolvates are pharmaceutically acceptable solvates including hydrates.

“Subject” as used herein, means a human or a non-human mammal, e.g., adog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-humanprimate or a bird, e.g., a chicken, as well as any other vertebrate orinvertebrate.

By “therapeutically effective amount” or “pharmaceutically effectiveamount” is typically one which is sufficient to achieve the desiredeffect and may vary according to the nature and severity of the diseasecondition, and the potency of the compound. It will be appreciated thatdifferent concentrations may be employed for prophylaxis than fortreatment of an active disease. This amount can further depend upon thepatient's height, weight, sex, age and medical history.

A therapeutic effect relieves, to some extent, one or more of thesymptoms of the disease, and includes curing a disease. “Curing” meansthat the symptoms of active disease are eliminated. However, certainlong-term or permanent effects of the disease may exist even after acure is obtained (such as extensive tissue damage).

“Treat,” “treatment,” or “treating,” as used herein refers toadministering a pharmaceutical composition for therapeutic purposes. Theterm “therapeutic treatment” refers to administering treatment to apatient already suffering from a disease thus causing a therapeuticallybeneficial effect, such as ameliorating existing symptoms, preventingadditional symptoms, ameliorating or preventing the underlying metaboliccauses of symptoms, postponing or preventing the further development ofa disorder and/or reducing the severity of symptoms that will or areexpected to develop.

Compounds

The compounds and compositions described herein can be used asanti-proliferative agents, e.g., anti-cancer and anti-angiogenesisagents, and as inhibitors of the Wnt signaling pathway, e.g., fortreating diseases or disorders associated with aberrant Wnt signaling.In addition, the compounds can be used as inhibitors of one or morekinases, kinase receptors, or kinase complexes (e.g., VEGF, CHK-1, CLK,HIPK, Abl, JAK and/or CDK complexes). Such compounds and compositionsare also useful for controlling cellular proliferation, differentiation,and/or apoptosis.

Some embodiments of the present invention include compounds, salts,pharmaceutically acceptable salts or pro-drug thereof of formula (Ia):

In some embodiments, R¹, R², R⁴, R⁶, R⁷, R⁸ and R⁹ are independentlyselected from the group consisting of H, C₁₋₉ alkyl, halide, —CF₃,—(C₁₋₉ alkyl)_(n)carbocyclylR¹³, —(C₁₋₉ alkyl)_(n)heterocyclylR¹³,—(C₁₋₉ alkyl)_(n)arylR¹³, —(C₁₋₉ alkyl)_(n)heteroarylR¹³, —(C₁₋₉alkyl)_(n)OR¹⁰, —(C₁₋₉ alkyl)_(n)SR¹⁰, —(C₁₋₉ alkyl)_(n)S(═O)R¹¹, —(C₁₋₉alkyl)_(n)SO₂R¹⁰, —(C₁₋₉ alkyl)_(n)N(R¹⁰)SO₂R¹⁰, —(C₁₋₉alkyl)_(n)SO₂N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)C(=A)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)C(=A)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)C(=A)R¹⁰, —NO₂, —CN, —(C₁₋₉ alkyl)_(n)CO₂R¹⁰ and —(C₁₋₉alkyl)_(n)C(=A)R¹⁰.

In some embodiments, R³ is selected from the group consisting of—NRS(═O)R¹⁴, —(C₁₋₉alkyl)R¹⁴, -carbocyclylR¹⁴R¹⁵, -heterocyclylR¹⁴R¹⁵,-arylR¹⁴R¹⁵ or -heteroarylR¹⁴R¹⁵.

In some embodiments, one of each R¹ and R², R² and R³, R³ and R⁴, R⁶ andR⁷, R⁷ and R⁸ or R⁸ and R⁹ are taken together to form a ring which isselected from the group consisting of aryl, heteroaryl,

wherein each bond represented by a dashed and solid line represents abond selected from the group consisting of a single bond and a doublebond.

In some embodiments, each R¹⁰ is independently selected from the groupconsisting of H, —C₁₋₉ alkyl, —CF₃, —(C₁₋₉ alkyl)_(n)carbocyclyl, —(C₁₋₉alkyl)_(n)heterocyclyl, —(C₁₋₉ alkyl)_(n)aryl and —(C₁₋₉alkyl)_(n)heteroaryl.

In some embodiments, each R¹¹ is independently selected from the groupconsisting of —C₁₋₉ alkyl, —CF₃, —(C₁₋₉ alkyl)_(n)carbocyclyl, —(C₁₋₉alkyl)_(n)heterocyclyl, —(C₁₋₉ alkyl)_(n)aryl and —(C₁₋₉alkyl)_(n)heteroaryl.

In some embodiments, each R¹² is independently selected from the groupconsisting of —OR¹⁰ and R¹⁰.

In some embodiments, each R¹³ is 1-5 substituents each selected from thegroup consisting of H, C₁₋₉ alkyl, halide, —CF₃, carbocyclylR¹³,heterocyclylR¹³, arylR¹³, heteroarylR¹³, —(C₁₋₉ alkyl)_(n)OR¹⁰, —(C₁₋₉alkyl)_(n)SR¹⁰, —(C₁₋₉ alkyl)_(n)S(═O)R¹¹, —(C₁₋₉ alkyl)_(n)SO₂R¹⁰,—(C₁₋₉ alkyl)_(n)N(R¹⁰)SO₂R¹⁰, —(C₁₋₉ alkyl)_(n)SO₂N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)C(=A)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)C(=A)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)C(=A)R¹⁰, —NO₂, —CN,—(C₁₋₉ alkyl)_(n)CO₂R¹ and —(C₁₋₉ alkyl)_(n)C(=A)R¹⁰.

In some embodiments, R¹⁴ is selected from the group consisting of—NR¹⁰C(=A)R¹⁰, —NR¹⁰S(═O)R¹¹, —NR¹⁰SO₂R¹⁰, —NR¹⁰C(═O)N(R¹⁶)₂,—NR¹⁰C(═S)N(R¹⁰)₂, —NR¹⁰C(═NR¹²)N(R¹⁰)₂, —N(R¹⁶)₂, —C(═O)NR¹⁰R¹⁷,—C(═S)N(R¹⁰)₂, —C(═NR¹²)N(R¹⁰)₂, —OC(=A)R¹⁰, —C(=A)R¹⁰, —NR¹⁰C(=A)OR¹⁰and —OC(=A)NR¹⁰R¹⁰.

In some embodiments, R¹⁵ is 1-4 substituents each selected from thegroup consisting of H, C₁₋₉ alkyl, halide, —CF₃, carbocyclylR¹³,heterocyclylR¹³, arylR¹³, heteroarylR¹³, —(C₁₋₉ alkyl)_(n)OR¹⁰, —(C₁₋₉alkyl)_(n)SR¹⁰, —(C₁₋₉ alkyl)_(n)S(═O)R¹¹, —(C₁₋₉ alkyl)_(n)SO₂R¹⁰,—(C₁₋₉ alkyl)_(n)N(R¹⁰)SO₂R¹⁰, —(C₁₋₉ alkyl)_(n)SO₂N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)C(=A)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)C(=A)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)C(=A)R¹⁰, —NO₂, —CN,—(C₁₋₉ alkyl)_(n)CO₂R¹ and —(C₁₋₉ alkyl)_(n)C(=A)R¹⁰.

In some embodiments, R¹⁶ is —C₁₋₉ alkyl.

In some embodiments, each R¹⁷ is independently selected from the groupconsisting of -heterocyclylR¹³, —(C₁₋₉ alkyl)heterocyclylR¹³ and —(C₁₋₉alkyl)carbocyclylR¹³.

In some embodiments, R¹⁸ and R¹⁹ are independently selected from thegroup consisting of H, C₁₋₉ alkyl, halide, —(C₁₋₉alkyl)_(n)carbocyclylR¹³, —(C₁₋₉ alkyl)_(n)heterocyclylR¹³, —(C₁₋₉alkyl)_(n)arylR¹³, —(C₁₋₉ alkyl)_(n)heteroarylR¹³, —(C₁₋₉alkyl)_(n)OR¹⁰, —(C₁₋₉ alkyl)_(n)SR¹⁰, —(C₁₋₉ alkyl)_(n)S(═O)R¹¹, —(C₁₋₉alkyl)_(n)SO₂R¹⁰, —(C₁₋₉ alkyl)_(n)N(R¹⁰)SO₂R¹⁰, —(C₁₋₉alkyl)_(n)SO₂N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)C(=A)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)C(=A)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)C(=A)R¹⁰, —NO₂, —CN, —(C₁₋₉ alkyl)_(n)CO₂R¹⁰ and —(C₁₋₉alkyl)_(n)C(=A)R¹⁰.

In some embodiments, R¹⁸ and R¹⁹ are taken together to form a ring whichis selected from the group consisting of benzene and pyridine.

In some embodiments, each A is independently selected from O, S andNR¹².

In some embodiments, Y¹, Y², Y³ and Y⁴ are independently selected fromthe group consisting of carbon and nitrogen with the proviso that atleast one of Y¹, Y², Y³ and Y⁴ are nitrogen.

In some embodiments, Y¹ is nitrogen and R⁶ is absent.

In some embodiments, Y² is nitrogen and R⁷ is absent.

In some embodiments, Y³ is nitrogen and R⁸ is absent.

In some embodiments, Y⁴ is nitrogen and R⁹ is absent.

In some embodiments, each n is 0 or 1.

Some embodiments of the present invention include compounds, salts,pharmaceutically acceptable salts or pro-drug thereof of formula (Ib):

In some embodiments, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ areindependently selected from the group consisting of H, C₁₋₉ alkyl,halide, —CF₃, —(C₁₋₉ alkyl)_(n)carbocyclylR¹³, —(C₁₋₉alkyl)_(n)heterocyclylR¹³, —(C₁₋₉ alkyl)_(n)arylR¹³, —(C₁₋₉alkyl)_(n)heteroarylR¹³, —(C₁₋₉ alkyl)_(n)OR¹⁰, —(C₁₋₉ alkyl)_(n)SR¹⁰,—(C₁₋₉ alkyl)_(n)S(═O)R¹¹, —(C₁₋₉ alkyl)_(n)SO₂R¹⁰, —(C₁₋₉alkyl)_(n)N(R¹⁰)SO₂R¹⁰, —(C₁₋₉ alkyl)_(n)SO₂N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)C(=A)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)C(=A)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)C(=A)R¹⁰, —NO₂, —CN,—(C₁₋₉ alkyl)_(n)CO₂R¹⁰ and —(C₁₋₉ alkyl)_(n)C(=A)R¹⁰.

In some embodiments, one of each R¹ and R², R² and R³, R³ and R⁴, R⁶ andR⁷, R⁷ and R⁸ or R⁸ and R⁹ are taken together to form a ring which isselected from the group consisting of aryl, heteroaryl,

wherein each bond represented by a dashed and solid line represents abond selected from the group consisting of a single bond and a doublebond.

In some embodiments, each R¹⁰ is independently selected from the groupconsisting of H, —C₁₋₉ alkyl, —CF₃, —(C₁₋₉ alkyl)_(n)carbocyclyl, —(C₁₋₉alkyl)_(n)heterocyclyl, —(C₁₋₉ alkyl)_(n)aryl and —(C₁₋₉alkyl)_(n)heteroaryl.

In some embodiments, each R¹¹ is independently selected from the groupconsisting of —C₁₋₉ alkyl, —CF₃, —(C₁₋₉ alkyl)_(n)carbocyclyl, —(C₁₋₉alkyl)_(n)heterocyclyl, —(C₁₋₉ alkyl)_(n)aryl and —(C₁₋₉alkyl)_(n)heteroaryl.

In some embodiments, each R¹² is independently selected from the groupconsisting of —OR¹⁰ and R¹⁰.

In some embodiments, each R¹³ is 1-5 substituents each selected from thegroup consisting of H, C₁₋₉ alkyl, halide, —CF₃, carbocyclylR¹³,heterocyclylR¹³, arylR¹³, heteroarylR¹³, —(C₁₋₉ alkyl)_(n)OR¹⁰, —(C₁₋₉alkyl)_(n)SR¹⁰, —(C₁₋₉ alkyl)_(n)S(═O)R¹¹, —(C₁₋₉ alkyl)_(n)SO₂R¹⁰,—(C₁₋₉ alkyl)_(n)N(R¹⁰)SO₂R¹⁰, —(C₁₋₉ alkyl)_(n)SO₂N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)C(=A)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)C(=A)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)C(=A)R¹⁰, —NO₂, —CN,—(C₁₋₉ alkyl)_(n)CO₂R¹⁰ and —(C₁₋₉ alkyl)_(n)C(=A)R¹⁰.

In some embodiments, R¹⁸ and R¹⁹ are independently selected from thegroup consisting of H, C₁₋₉ alkyl, halide, —(C₁₋₉alkyl)_(n)carbocyclylR¹³, —(C₁₋₉ alkyl)_(n)heterocyclylR¹³, —(C₁₋₉alkyl)_(n)arylR¹³, —(C₁₋₉ alkyl)_(n)heteroarylR¹³, —(C₁₋₉alkyl)_(n)OR¹⁰, —(C₁₋₉ alkyl)_(n)SR¹⁰, —(C₁₋₉ alkyl)_(n)S(═O)R¹¹, —(C₁₋₉alkyl)_(n)SO₂R¹⁰, —(C₁₋₉ alkyl)_(n)N(R¹⁰)SO₂R¹⁰, —(C₁₋₉alkyl)_(n)SO₂N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)C(=A)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)C(=A)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)C(=A)R¹⁰, —NO₂, —CN, —(C₁₋₉ alkyl)_(n)CO₂R¹⁰ and —(C₁₋₉alkyl)_(n)C(=A)R¹⁰.

In some embodiments, R¹⁸ and R¹⁹ are taken together to form a ring whichis selected from the group consisting of benzene and pyridine.

In some embodiments, each A is independently selected from O, S andNR¹².

In some embodiments, Y¹, Y², Y³ and Y⁴ are independently selected fromthe group consisting of carbon and nitrogen with the proviso that atleast one of Y¹, Y², Y³ and Y⁴ are nitrogen.

In some embodiments, Y¹ is nitrogen and R⁶ is absent.

In some embodiments, Y² is nitrogen and R⁷ is absent.

In some embodiments, Y³ is nitrogen and R⁸ is absent.

In some embodiments, Y⁴ is nitrogen and R⁹ is absent.

In some embodiments, each n is 0 or 1.

Illustrative compounds of Formula (Ia) and (Ib) are shown in Table 1.

TABLE 1 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

Compound Preparation

The starting materials used in preparing the compounds of the inventionare known, made by known methods, or are commercially available. It willbe apparent to the skilled artisan that methods for preparing precursorsand functionality related to the compounds claimed herein are generallydescribed in the literature. The skilled artisan given the literatureand this disclosure is well equipped to prepare any of the compounds.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out manipulations without further direction,that is, it is well within the scope and practice of the skilled artisanto carry out these manipulations. These include reduction of carbonylcompounds to their corresponding alcohols, oxidations, acylations,aromatic substitutions, both electrophilic and nucleophilic,etherifications, esterification and saponification and the like. Thesemanipulations are discussed in standard texts such as March's AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure 6^(th) Ed., JohnWiley & Sons (2007), Carey and Sundberg, Advanced Organic Chemistry5^(th) Ed., Springer (2007), Comprehensive Organic Transformations: AGuide to Functional Group Transformations, 2^(nd) Ed., John Wiley & Sons(1999) (incorporated herein by reference in its entirety) and the like.

The skilled artisan will readily appreciate that certain reactions arebest carried out when other functionality is masked or protected in themolecule, thus avoiding any undesirable side reactions and/or increasingthe yield of the reaction. Often the skilled artisan utilizes protectinggroups to accomplish such increased yields or to avoid the undesiredreactions. These reactions are found in the literature and are also wellwithin the scope of the skilled artisan. Examples of many of thesemanipulations can be found for example in T. Greene and P. WutsProtecting Groups in Organic Synthesis, 4th Ed., John Wiley & Sons(2007), incorporated herein by reference in its entirety.

The following example schemes are provided for the guidance of thereader, and represent preferred methods for making the compoundsexemplified herein. These methods are not limiting, and it will beapparent that other routes may be employed to prepare these compounds.Such methods specifically include solid phase based chemistries,including combinatorial chemistry. The skilled artisan is thoroughlyequipped to prepare these compounds by those methods given theliterature and this disclosure. The compound numberings used in thesynthetic schemes depicted below are meant for those specific schemesonly, and should not be construed as or confused with same numberings inother sections of the application.

To further illustrate this invention, the following examples areincluded. The examples should not, of course, be construed asspecifically limiting the invention. Variations of these examples withinthe scope of the claims are within the purview of one skilled in the artand are considered to fall within the scope of the invention asdescribed, and claimed herein. The reader will recognize that theskilled artisan, armed with the present disclosure, and skill in the artis able to prepare and use the invention without exhaustive examples.

Trademarks used herein are examples only and reflect illustrativematerials used at the time of the invention. The skilled artisan willrecognize that variations in lot, manufacturing processes, and the like,are expected. Hence the examples, and the trademarks used in them arenon-limiting, and they are not intended to be limiting, but are merelyan illustration of how a skilled artisan may choose to perform one ormore of the embodiments of the invention.

¹H nuclear magnetic resonance spectra (NMR) were measured in theindicated solvents on a Bruker NMR spectrometer (Avance TM DRX300, 300MHz for 1H). Peak positions are expressed in parts per million (ppm)downfield from tetramethylsilane. The peak multiplicities are denoted asfollows, s, singlet; d, doublet; t, triplet; m, multiplet.

The following abbreviations have the indicated meanings:

brine=saturated aqueous sodium chloride

CDCl₃=deuterated chloroform

DCM=dichloromethane

DHP=3,4-dihydro-2H-pyran

DMF=N,N-dimethylformamide

DMSO-d₆=deuterated dimethylsulfoxide

ESIMS=electron spray mass spectrometry

EtOAc=ethyl acetate

Et₃SiH=triethylsilane

HCl=hydrochloric acid

HOAc=acetic acid

KOH=potassium hydroxide

K₃PO₄=potassium phosphate

LAH=lithium aluminum hydride

MeOH=methanol

MgSO₄=magnesium sulfate

Na₂CO₃=sodium carbonate

NaHCO₃=sodium bicarbonate

NaHSO₃=sodium bisulfite

NaOAc=sodium acetate

NMR=nuclear magnetic resonance

Pd/C=palladium on carbon

PdCl₂(dppf)₂=1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride

Pd(PPh₃)₂Cl₂=dichloro-bis(triphenylphosphine)palladium (II)

Pd(PPh₃)₄=tetrakis(triphenylphosphine)palladium(O)

PPTS=pyridinium p-toluenesulfonate

rt=room temperature

TFA=trifluoroacetic acid

THF=tetrahydrofuran

TLC=thin layer chromatography

The following example schemes are provided for the guidance of thereader, and collectively represent an example method for making thecompounds provided herein. Furthermore, other methods for preparingcompounds of the invention will be readily apparent to the person ofordinary skill in the art in light of the following reaction schemes andexamples. Unless otherwise indicated, all variables are as definedabove.

General Procedures

Compounds of Formula Ia of the present invention can be prepared asdepicted in Scheme 1.

Scheme 1 describes a method for preparation of indazole derivatives(VII) by first reacting5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (I) withbis(pinacolato)diboron to form the borate ester (II). Suzuki couplingwith various bromides (III) yields indazole derivatives (IV). Aldehyde(IV) is reacted with various 1,2-diamines (V) to produce (VI). Finaldeprotection of the pyrazole nitrogen yields the desired indazolederivatives (VII).

ILLUSTRATIVE COMPOUND EXAMPLES

Preparation of intermediate (I) is depicted below in Scheme 2.

Reagents and conditions: a) NHOMe(Me).HCl, carbonyldiimidazole,imidazole, DMF, 65° C.; b) Bis(trifluoroacetoxy)iodobenzene, 12, DCMr.t; c) DHP, PPTS, DCM, refluxed; d) LAH, THF, 0° C.

Step a

1H-indazole-3-carboxylic acid (VIII) (100 g, 617 mmol) in DMF wastreated with carbonyldiimidazole (110 g, 678 mmol) at r.t. until theevolution of gas ceased (ca. 15 minutes). The reaction was heated to60-65° C. for two hours and then allowed to cool to r.t.N,O-Dimethylhydroxylamine-HCl (66.2 g, 678 mmol) was added as a solidand the mixture was heated to 65° C. for 3 hours. The reaction wasconcentrated to a paste and taken up in DCM, and washed subsequentlywith water and 2N HCl. The product could be seen coming out of solution.The solid was filtered and rinsed separately with EtOAc. The EtOAc andDCM layers were separately washed with sodium bicarbonate followed bybrine, dried over MgSO₄ and concentrated under reduced pressure. Theresulting solids were combined, triturated with 1:1 mixture ofDCM-ether, filtered, and dried to produceN-methoxy-N-methyl-1H-indazole-3-carboxamide (IX) as a white solid (100g, 487 mmol, 79% yield). ¹H NMR (DMSO-d₆) δ ppm 3.46 (s, 3H), 3.69-3.85(m, 3H), 7.13-7.31 (m, 1H), 7.41 (t, J=7.25 Hz, 1H), 7.56-7.65 (m, 1H),7.93-8.08 (m, 1H); ESIMS found for C₁₀H₁₁N₃O₂ m/z 206 (M+H).

Step b

To the N-methoxy-N-methyl-1H-indazole-3-carboxamide (IX) (20 g, 97.4mmol) in 1 L DCM was added bis(trifluoroacetoxy)iodobenzene (46 g, 107mmol) followed by portionwise addition of iodine (14.84 g, 58.5 mmol) atr.t. After 1 hour, 600 mL of saturated NaHSO₃ was added and a solidbegan to precipitate which was filtered and rinsed with excess DCM. Thefiltrate was washed with brine, dried over MgSO₄, concentrated and theremaining solid was triturated with a minimal amount of DCM. Thecombined solids were dried under vacuum over KOH to produce5-iodo-N-methoxy-N-methyl-1H-indazole-3-carboxamide (X) as a white solid(23.2 g, 70 mmol, 72% yield). ¹H NMR (DMSO-d₆) δ ppm 3.45 (s, 4H), 3.77(s, 4H), 7.45-7.54 (m, 1H), 7.66 (dd, J=8.81, 1.51 Hz, 1H), 8.40 (d,J=1.01 Hz, 1H); ESIMS found for C₁₀H₁₀N₃O₂ m/z 331 (M+H).

Step c

A mixture of 5-iodo-N-methoxy-N-methyl-1H-indazole-3-carboxamide (X)(16.5 g, 50 mmol), 3,4-dihydro-2H-pyran (10.3 mL, 113 mmol) and PPTS(0.12 g, 0.6 mmol) in DCM was heated to reflux for 5 hours. The solutionwas poured into a saturated NaHCO₃ solution, the layers were separated,and the aqueous layer was extracted with DCM. The combined organiclayers were washed with 5% aqueous citric acid and brine, dried overMgSO₄, and concentrated. The crude product was purified on a silica gelcolumn (100% EtOAc→3:97 MeOH:DCM) to provide5-iodo-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide(XI) as a white viscous oil (19.1 g, 46 mmol, 92% yield). ¹H NMR(DMSO-d₆) δ ppm 1.28-1.84 (m, 6H), 3.43 (s, 3H), 3.60-4.04 (s, 5H),5.86-6.08 (m, 1H), 7.45-7.87 (m, 2H), 8.39 (s, 1H); ESIMS found forC₁₅H₁₈IN₃O₃ m/z 416 (M+H).

Step d

Lithium aluminum hydride (160 mg, 4.21 mmol) was added in portions to acooled (0° C.) solution of5-iodo-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide(XI) (1.46 g, 3.5 mmol) in THF. Stirring was continued at 0° C. untilthe reaction was completed, approximately 30 min. The reaction wasquenched by the slow addition of EtOAc at 0° C., and the whole mixturewas poured into 0.4 N NaHSO₄. The organic layer was washed with brine,dried over MgSO₄, concentrated, and purified on a silica gel column(100% EtOAc→3:97 MeOH:DCM) to give5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (I) as awhite solid (0.90 g, 3.15 mmol, 72% yield). ¹H NMR (DMSO-d₆) δ ppm1.50-1.71 (m, 2H), 1.71-1.87 (m, 1H), 1.97-2.15 (m, 2H), 2.31-2.42 (m,1H), 3.66-3.99 (m, 2H), 5.96-6.17 (m, 1H), 7.78 (d, J=6 Hz, 1H), 7.84(d, J=6 Hz, 1H), 8.50 (s, 1H), 10.13 (s, 1H); ESIMS found forC₁₃H₁₃IN₂O₂ m/z 357 (M+H).

Preparation of intermediate (XV) is depicted below in Scheme 3.

Reagents and conditions: a) HOAc, NaOAc, Br₂, 100° C., 28 h, b)1,4-Dioxane, pyridyl-3-boronic acid, Na₂CO₃, H₂O, Pd(PPh₃)₂Cl₂, reflux.,15 h, c) MeOH, Pd/C, H₂, rt, 15 h

Step a

A mixture of 3-nitropyridin-4-amine (XII) (10 g, 71.94 mmol) and aceticacid (120 ml) was added to a sealed tube followed by addition of NaOAc(29.50 g, 93.52 mmol) and dropwise addition of bromine (4.7 ml 359.7mmol) under stirring. The sealed tube was heated at 100° C. for 28 huntil TLC showed consumption of starting material. The reaction mixturewas concentrated to obtain a solid which was dissolved in water,basified with NaHCO₃ and extracted with ethyl acetate. The combinedorganic extracts were dried and concentrated to produce3-bromo-5-nitropyridin-4-amine (XIII) as a yellow solid (12 g, 55 mmol,77% yield). ¹H NMR (DMSO-d₆) δ ppm 9.19 (s, 1H), 8.58 (s, 1H); ESIMSfound for C₅H₄BrN₃O₂ m/z 217, 219 (M+, M+2).

Step b

A solution of 3-bromo-5-nitropyridin-4-amine (XIII) (6 g, 26 mmol),pyridin-3-ylboronic acid (3.54 g, 29 mmol), 1 N Na₂CO₃ solution (78 ml)and 1,4-dioxane (150 mL) was degassed with argon thrice. Pd(PPh₃)₂Cl₂(927 mg, 5 mmol %) was added to the reaction and the solution wasrefluxed for 15 h until TLC showed the reaction was complete. Thereaction was passed through a pad of Celite and then concentrated underreduced pressure. The reaction mixture was concentrated and the residuewas taken up in ethyl acetate. The organic extract was washed withwater, dried and concentrated under vacuum. The crude product waspurified on a silica gel column (100% EtOAc→2:98 MeOH:DCM) to give5-nitro-3,3′-bipyridin-4-amine (XIV) as a yellow solid (5 g, 23.1 mmol,87% yield). ¹H NMR (CDCl₃, 400 MHz,) δ ppm 9.31 (s, 1H), 8.80-8.79 (m,1H), 8.70 (s, 1H), 8.23 (s, 1H), 7.80-7.73 (m, 1H), 7.52-7.48 (m, 1H).ESIMS found C₁₀H₈N₄O₂ m/z 216.95 (M+H).

Step c

To a solution of 5-nitro-3,3′-bipyridin-4-amine (XIV) (5 g, 23 mmol) inMeOH (20 mL) was added 10% Pd/C. The solution was purged with hydrogenand stirred at r.t. under hydrogen for 15 h. The suspension was filteredthrough Celite and the concentrated under vacuum to produce3,3′-bipyridine-4,5-diamine (XV) as off white solid (3.3 g, 17.7 mmol,76% yield). ¹H NMR (DMSO-d₆, 400 MHz,): δ 8.63-8.53 (m, 1H), 7.90-7.83(m, 1H), 7.75 (s, 1H), 7.58 (s, 1H), 7.48-7.43 (m, 2H), 6.13 (bs, 2H),5.31 (bs, 2H). ESIMS found C₁₀H₁₀N₄ m/z 187.10 (M+H).

Preparation of intermediate (XVII) is depicted below in Scheme 4.

Step 1-2

To a solution of 5-bromonicotinic acid (XVI) (1.01 g, 5 mmol) in dry DCM(10 mL) under nitrogen was added oxalyl chloride (0.654 mL, 7.5 mmol)followed by dry DMF (0.1 mL). The solution was stirred at r.t. for 30min. The solvent was evaporated under vacuum before adding dry pyridine(10 mL) followed by cyclopropylmethanamine (0.39 mL, 4.5 mmol). Thesolution was stirred at r.t. under nitrogen for 2 h. The solution waspoured into ice water, basified with sat. aq. NaHCO₃ and extracted withDCM. The combined organic phases were dried over MgSO₄, concentrated anddried under vacuum to yield 5-bromo-N-(cyclopropylmethyl) nicotinamide(XVII) as an off-white solid (0.82 g, 3.2 mmol, 71% yield). ¹H NMR(DMSO-d₆) δ ppm −0.07-0.07 (m, 2H), 0.15-0.29 (m, 2H), 0.68-0.88 (m,1H), 2.93 (t, J=6.22 Hz, 2H), 8.20 (t, J=1.88 Hz, 1H), 8.62 (d, J=1.70Hz, 2H), 8.75 (s, 1H); ESIMS found C₁₀H₁₁BrN₂O m/z 254, 256 (M+, M+2).

Preparation of intermediate (XX) is depicted below in Scheme 5.

Step 1

3-Amino-5-bromo pyridine (XVIII) (1 eq) was dissolved in DCM and cooledto 0° C. before adding pyridine (2.2 eq) and isobutyryl chloride (XIX)(1.1 eq). The reaction mixture was stirred at r.t. for 15 h until TLCshowed the reaction was complete. The reaction mixture was diluted withDCM and washed with water. The organic extract was dried, concentratedand purified by column chromatography using silica gel (100-200 mesh) toafford N-(5-bromopyridin-3-yl)isobutyramide (XX) as a off white solid,(71% yield). ¹H NMR (CDCl₃) δ ppm 8.55-8.35 (m, 3H), 7.32 (s, 1H),2.59-2.48 (m, 1H), 1.28-1.27 (d, 6H); ESIMS found C₉H₁₁BrN₂O m/z243.05(M+H).

The following intermediates were prepared in accordance with theprocedure described in the above Scheme 5.

N-(5-bromopyridin-3-yl)pivalamide (XXI): Off white solid, (67%, yield),¹H NMR (CDCl₃, 400 MHz) δ ppm 8.48-8.39 (m, 3H), 7.48 (bs, 1H), 1.32 (s,9H); ESIMS found C₁₀H₁₃BrN₂O m/z 256.80 (M+H).

N-(5-bromopyridin-3-yl)-3-methylbutanamide (XXII): Off white solid, (67%yield), ¹H NMR (CDCl₃, 400 MHz) δ ppm 8.55-8.42 (m, 3H), 7.62 (s, 1H),2.31-2.18 (m, 3H), 1.02-1.01 (d, J=6 Hz, 6H); ESIMS found C₁₀H₁₃BrN₂Om/z 258.80 (M+H).

N-(5-bromopyridin-3-yl)-3,3-dimethylbutanamide (XXIII): Light yellowsolid, (64%, yield), ¹H NMR (CDCl₃, 400 MHz) δ ppm 8.48 (s, 1H), 8.40(s, 1H), 7.62 (s, 1H), 7.20 (bs, 1H), 2.26 (s, 3H), 1.10 (s, 9H); ESIMSfound C₁₁H₁₅BrN₂O m/z 272.80 (M+H).

N-(5-bromopyridin-3-yl)butyramide (XXIV): Yellow solid, (86%, yield), ¹HNMR (CDCl₃, 400 MHz) δ ppm 8.48-8.39 (m, 3H), 7.38 (bs, 1H), 2.40-2.36(t, J=7.2 Hz, 2H), 1.81-1.72 (m, 2H), 1.03-0.98 (t, J=7.2 Hz, 3H); ESIMSfound C₉H₁₁BrN₂O m/z 242.90 (M+H).

N-(5-bromopyridin-3-yl)pentanamide (XXV): Off white solid, (75%, yield),¹H NMR (CDCl₃, 400 MHz) δ ppm 8.47-8.39 (m, 3H), 7.33 (bs, 1H),2.41-2.38 (t, 2H, J=7.6 Hz, 2H), 1.75-1.68 (m, 2H), 1.45-1.36 (m, 2H),0.97-0.93 (t, J=7.2 Hz, 3H); ESIMS found C₁₀H₁₃BrN₂O m/z 256.90 (M+H).

N-(5-bromopyridin-3-yl)cyclopropanecarboxamide (XXVI): Off white solid,(83% yield), ¹H NMR (CDCl₃, 400 MHz) δ ppm 8.46-8.39 (m, 3H), 7.54 (bs,1H), 1.56-1.50 (m, 1H), 1.13-1.07 (m, 2H), 0.96-0.90 (m, 2H); ESIMSfound C₉H₉BrN₂O m/z 240.85 (M+H).

N-(5-bromopyridin-3-yl)cyclobutanecarboxamide (XXVII): Off white solid,(54% yield), ¹H NMR (CDCl₃, 400 MHz) δ ppm 8.97-8.39 (m, 3H), 7.21 (bs,1H), 3.20-3.16 (m, 1H), 2.42-2.24 (m, 4H), 2.05-1.94 (m, 2H); ESIMSfound C₁₀H₁₁BrN₂O m/z 256.90 (M+H).

N-(5-bromopyridin-3-yl)cyclohexanecarboxamide (XXVIII): light yellowsolid, (89% yield), ¹H NMR (CDCl₃, 400 MHz) δ ppm 8.49-8.38 (m, 3H),7.61 (bs, 1H), 2.30-2.23 (dd, 1H, J=3.2 Hz, J=11.6 Hz, 1H), 1.96-1.49(m, 4H), 1.34-1.19 (m, 3H); ESIMS found C₁₂H₁₅BrN₂O m/z 284.75 (M+H).

N-(5-bromopyridin-3-yl)benzamide (XXIX): Off white solid, (85%, yield),¹H NMR (CDCl₃, 400 MHz) δ ppm 8.58-8.57 (m, 2H), 8.44-4.43 (d, J=1.6 Hz,1H), 8.03 (bs, 1H), 7.88-7.86 (d, J=7.2 Hz, 2H), 7.61-7.49 (m, 3H).;ESIMS found C₁₂H₉BrN₂O m/z 278.75 (M+H).

N-(5-bromopyridin-3-yl)-2-phenylacetamide (XXX): Off white solid, (59%,yield), ¹H NMR (CDCl₃, 400 MHz) δ ppm 8.37-8.31 (m, 3H), 7.41-7.30 (m,6H), 3.75 (s, 2H); ESIMS found C₁₃H₁₁BrN₂O m/z 292.72 (M+H).

Example 1

Preparation of compound (3) is depicted below in Scheme 6.

Reagents and conditions: a) KOAc, PdCl₂(dppf)₂, DMF, 80° C., 2 h; b)K₂PO₄, Pd(PPh₃)₄, DMF, H₂O, 90° C., 3 h; c) DMF, sulfur, 140° C., ON; d)Et₃SiH, DCM, TFA, r.t., 2 h.

Step a-b

A solution of5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (I)(1.068 g, 3.0 mmol), bis(pinacolato)diboron (0.914 g, 3.6 mmol), KOAc(0.883 g, 9.0 mmol) and dry DMF (20 mL) was purged with nitrogen.PdCl₂(dppf)₂ was added to the reaction and purged again with nitrogen.The solution was heated at 80° C. for 2 h. Once TLC showed thedisappearance of (I), the solution was cooled to r.t. To this solutionwas added K₃PO₄ (0.955 g, 4.5 mmol), 5-bromo-N-(cyclopropylmethyl)nicotinamide (XVII) (0.765 g, 3.0 mmol), Pd(PPh₃)₄ (104 mg, 0.09 mmol)and water (2 mL). The solution was purged with nitrogen and heated at90° C. for 3 h. The reaction was passed through a pad of Celite and thenconcentrated under reduced pressure. The residue was dissolved in DCMand washed with water and brine, dried over MgSO₄ and then evaporatedunder vacuum. The crude product was purified on a silica gel column(100% EtOAc→2:98 MeOH:DCM) to giveN-(cyclopropylmethyl)-5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)nicotinamide(XXXI) as a yellow solid (1.09 g, 2.7 mmol, 90% yield). ¹H NMR (DMSO-d₆)δ ppm 0.20-0.31 (m, 2H), 0.35-0.57 (m, 2H), 1.65 (m, 2H), 1.74-1.87 (m,1H), 2.10 (d, J=12.06 Hz, 2H), 2.35-2.44 (m, 1H), 3.10-3.27 (m, 3H),3.78-3.99 (m, 2H), 6.14 (d, J=7.35 Hz, 1H), 7.90-8.14 (m, 2H), 8.50 (d,J=12.5, 2H), 9.05 (dd, J=14.60, 1.98 Hz, 2H), 10.25 (s, 1H); ESIMS foundC₂₃H₂₄N₄O₃ m/z 405 (M+H).

Step c

A solution ofN-(cyclopropylmethyl)-5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)nicotinamide(XXXI) (0.404 g, 1.0 mmol), 3,3′-bipyridine-4,5-diamine (XV) (186 mg,1.0 mmol) and sulfur (35 mg, 1.1 mmol) in dry DMF (10 mL) was heated at140° C. overnight. The reaction was cooled and evaporated under vacuum.The residue was suspended in water, sonicated and filtered. The solidwas washed with cold water and dried under vacuum. The crude product wasdissolved in DCM and cooled to 4° C. overnight to getN-(cyclopropylmethyl)-5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)nicotinamide (XXXII) as a brown solid (130 mg, 0.23 mmol, 23% yield). ¹HNMR (DMSO-d₆) δ ppm 0.19-0.37 (m, 2H), 0.36-0.58 (m, 2H), 0.97-1.115 (m,1H), 1.67 (br, 2H), 2.14 (d, J=9.98 Hz, 2H), 2.40-2.46 (m, 1H),3.20-3.33 (m, 3H), 3.75-4.14 (m, 2H), 6.13 (d, J=8.29 Hz, 1H), 7.60 (dd,J=7.82, 4.80 Hz, 1H), 7.92-8.12 (m, 3H), 8.20 (d, J=8.67 Hz, 1H),8.55-8.67 (m, 2H), 8.94 (br s, 3H), 9.06 (d, J=1.88 Hz, 1H), 9.19 (d,J=1.87 Hz, 1H); ESIMS found C₃₃H₃₀N₈O₂ m/z 571 (M+H).

Step d

A solution ofN-(cyclopropylmethyl)-5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)nicotinamide (XXXII) (125 mg, 0.22 mmol) and Et₃SiH (87 μL, 0.55 mmol)in DCM (5 mL) was slowly added TFA (2.5 mL). The reaction was stirred atr.t. for 3 h. The reaction was evaporated under vacuum and the residuewas treated with water, basified with aq. ammonia. The solids werefiltered, washed with cold water and dried. The crude product was heatedin MeOH and filtered hot to remove impurities. The hot MeOH solution wasallowed to slowly cool to r.t. to produceN-(cyclopropylmethyl)-5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)nicotinamide(3) as a off-white solid (48 mg, 0.10 mmol, 44% yield). ¹H NMR (DMSO-d₆)δ ppm 0.28 (d, J=4.28 Hz, 2H), 0.42-0.58 (m, 2H), 1.09 (br s, 1H), 3.25(t, J=6.06 Hz, 2H), 7.50-7.70 (m, 1H), 7.79-8.11 (m, 2H), 8.48-8.68 (m,1H), 8.69-8.82 (m, 1H), 8.81-8.97 (m, 3H), 9.00-9.18 (m, 2H), 9.46 (brs, 1H); ESIMS found C₂₈H₂₂N₈O m/z 487 (M+H).

The following compounds was prepared in accordance with the proceduredescribed in the above Example 1.

5-(3-(3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)-N-(piperidin-4-yl)nicotinamide1

¹H NMR (DMSO-d₆) δ ppm 1.55-1.75 (m, 2H), 1.90-2.05 (m, 2H), 2.78-2.90(t, 2H), 3.15-3.25 (d, 2H), 3.95-4.12 (m, 1H), 7.65 (br s, 1H), 7.87(dd, 2H), 8.31 (d, 1H), 8.53 (s, 1H), 8.79 (s, 1H), 8.98 (s, 2H), 9.13(s, 1H); ESIMS found for C₂₄H₂₂N₈O m/z 439 (M+H).

5-(3-(3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)-N-(cyclohexylmethyl)nicotinamide 2

¹H NMR (DMSO-d₆) δ ppm 0.98-1.15 (m, 2H), 1.2-1.39 (m, 3H), 1.64-1.89(m, 6H), 3.21-3.35 (m, 2H), 7.73 (d, 1H), 7.82 (d, 1H), 7.88 (d, 1H),8.34 (s, 1H), 8.62 (s, 1H), 8.86 (s, 1H), 8.96 (s, 1H), 8.99 (s, 1H),9.12 (s, 1H); ESIMS found for C₂₆H₂₅N₇O m/z 452 (M+H).

N-(5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide4

¹H NMR (DMSO-d₆) δ ppm 1.15 (t, J=7.16 Hz, 3H), 2.40 (q, 2H), 7.60 (brs, 1H), 7.85 (br s, 3H), 8.39-8.54 (m, 1H), 8.66 (br s, 2H), 8.77 (s,1H), 8.82 (s, 1H), 8.97 (br s, 1H); ESIMS found for C₂₆H₂₀N₈O m/z 461(M+H).

N-(5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide11

Dark brown solid (40% yield). ¹H NMR (DMSO-d₆, 400 MHz,) δ ppm 14.01 (brs, 1H), 13.79 (br s, 1H), 10.19 (s, 1H), 9.42 (s, 1H), 8.87-8.47 (m,8H), 7.83-7.78 (m, 2H), 7.57-7.54 (m, 1H), 2.69-2.62 (m, 2H), 1.14-1.13(d, J=6.8 Hz, 6H). ESIMS found C₂₇H₂₂N₈O m/z 475.10 (M+H).

N-(5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide12

Dark brown solid (23% yield). ¹H NMR (DMSO-d₆, 400 MHz,) δ ppm 14.03 (s,1H), 13.80 (s, 1H), 10.59 (s, 1H), 9.45 (s, 1H), 8.92-8.65 (m 7H), 8.47(s, 1H), 7.83 (s, 2H), 7.57 (s, 1H), 1.88-1.86 (m, 1H), 0.88-0.87 (m,4H). ESIMS found C₂₇H₂₀N₈O m/z 473.15 (M+H).

3-methyl-N-(5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide15

Dark brown solid (14% yield). ¹H NMR (DMSO-d₆, 400 MHz,) δ ppm 14.03 (s,1H), 13.78 (br s, 1H), 10.24 (s, 1H), 9.46 (s, 1H), 8.89-8.76 (m, 4H),8.75-8.39 (m, 4H), 7.86-7.82 (m, 2H), 7.59-7.58 (m, 1H), 2.30-2.28 (d,J=6.8 Hz, 2H), 2.18-2.12 (m, 1H), 0.99-097 (d, J=6.4 Hz, 6H). ESIMSfound C₂₈H₂₄N₈O m/z 489.20 (M+H).

N-(5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide16

Dark brown solid (30% yield). ¹H NMR (DMSO-d₆, 400 MHz,) δ ppm 14.04 (s,1H), 13.80 (s, 1H), 10.63 (s, 1H), 9.45 (s, 1H), 9.00-8.74 (m, 6H), 8.63(s, 1H), 8.36 (s, 1H), 8.07-8.05 (m, 2H), 7.88-7.86 (m, 2H), 7.67-7.52(m, 4H). ESIMS found C₃₀H₂₀N₈O m/z 509.05 (M+H).

N-(5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide17

Dark brown solid (43% yield). ¹H NMR (DMSO-d₆, 400 MHz,) δ ppm 14.03 (s,1H), 13.79 (br s, 1H), 9.57 (s, 1H), 9.46 (s, 1H), 8.92-8.81 (m, 4H),8.75-8.49 (m, 4H), 7.84 (s, 2H), 7.59-7.56 (m, 1H), 1.29 (s, 9H). ESIMSfound C₂₈H₂₄N₈O m/z 489.15 (M+H).

3,3-dimethyl-N-(5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide18

Dark brown solid (32% yield). ¹H NMR (DMSO-d₆, 400 MHz,) δ ppm 14.03 (s,1H), 13.77 (s, 1H), 10.18 (s, 1H), 9.46 (s, 1H), 8.89-8.75 (m, 4H),8.65-8.40 (m, 2H), 7.86-7.79 (m, 2H), 7.59-7.56 (m, 2H), 2.29 (s, 2H),1.06 (s, 9H). ESIMS found C₂₉H₂₆N₈O m/z 503.15 (M+H).

N-(5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide19

Off white solid (17% yield). ¹H NMR (DMSO-d₆, 400 MHz,) δ ppm 14.04 (s,1H), 13.78 (s, 1H), 10.20 (s, 1H), 9.45 (s, 1H), 8.89-8.51 (m, 7H), 7.83(s, 2H), 7.59 (s, 2H), 1.90-1.66 (m, 5H), 1.47-1.22 (m, 6H). ESIMS foundC₃₀H₂₆N₈O m/z 515.15 (M+H).

N-(5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide20

Dark brown solid (34% yield). ¹H NMR (DMSO-d₆, 400 MHz,) δ ppm 14.07 (s,1H), 10.26 (s, 1H), 9.40 (s, 1H), 8.96 (s, 1H), 8.80-8.65 (m, 6H), 8.48(s, 2H), 7.87-7.81 (m, 2H), 7.62-7.59 (m, 1H), 2.41-2.38 (t, J=7.2 Hz,2H), 1.70-1.64 (m, 2H), 0.98-0.94 (t, J=7.2 Hz, 3H) ESIMS foundC₂₇H₂₂N₈O m/z 475.10 (M+H).

N-(5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide21

Off white solid (21% yield). ¹H NMR (DMSO-d₆, 400 MHz,) δ ppm 13.09 (s,1H), 13.06 (s, 1H), 10.11 (s, 1H), 9.43 (bs, 1H), 8.92-8.78 (m 6H), 8.49(s, 2H), 7.82 (s, 2H), 7.58-7.56 (m, 1H), 2.31-2.27 (m, 4H), 2.19-2.17(m, 2H), 2.02-1.95 (m, 1H). ESIMS found C₂₈H₂₂N₈O m/z 487.10 (M+H).

2-phenyl-N-(5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide22

Off white solid (40% yield). ¹H NMR (DMSO-d₆, 400 MHz,) δ ppm 13.99 (s,1H), 13.00 (s, 1H), 10.58 (s, 1H), 9.41 (s, 1H), 8.90-8.49 (m, 8H),7.85-7.83 (m, 2H), 7.52-7.27 (m, 6H), 3.76 (s, 2H). ESIMS foundC₃₁H₂₂N₈O m/z 523.15 (M+H).

N-(5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide23

Dark brown solid (28% yield). ¹H NMR (DMSO-d₆, 400 MHz,) δ ppm 14.05 (s,1H), 13.01 (s, 1H), 10.26 (s, 1H), 9.39 (s, 1H), 8.95-8.65 (m 7H), 8.47(s, 1H), 7.86-7.80 (m, 2H), 7.61-7.58 (m, 1H), 2.43-2.40 (t, J=7.2 Hz,2H), 1.65-1.59 (m, 2H), 1.40-1.34 (m, 2H), 0.94-0.90 (t, J=7.2 Hz, 3H).ESIMS found C₂₈H₂₄N₈O m/z 489.15 (M+H).

Administration and Pharmaceutical Compositions

Some embodiments include pharmaceutical compositions comprising: (a) asafe and therapeutically effective amount of the indazole, or itscorresponding enantiomer, diastereoisomer or tautomer, orpharmaceutically acceptable salt; and (b) a pharmaceutically acceptablecarrier.

Administration of the compounds disclosed herein or the pharmaceuticallyacceptable salts thereof can be via any of the accepted modes ofadministration for agents that serve similar utilities including, butnot limited to, orally, subcutaneously, intravenously, intranasally,topically, transdermally, intraperitoneally, intramuscularly,intrapulmonarilly, vaginally, rectally, or intraocularly. Oral andparenteral administrations are customary in treating the indications.

Compounds of the invention intended for pharmaceutical use may beadministered as crystalline or amorphous products. Pharmaceuticallyacceptable compositions include solid, semi-solid, liquid and aerosoldosage forms, such as, e.g., tablets, capsules, powders, liquids,suspensions, suppositories, aerosols or the like. They may be obtained,for example, as films by methods such as precipitation, crystallization,freeze drying, spray drying, or evaporative drying. Microwave or radiofrequency drying may be used for this purpose. The compounds can also beadministered in sustained or controlled release dosage forms, includingdepot injections, osmotic pumps, pills, transdermal (includingelectrotransport) patches, and the like, for prolonged and/or timed,pulsed administration at a predetermined rate. Preferably, thecompositions are provided in unit dosage forms suitable for singleadministration of a precise dose.

The compounds can be administered either alone or more typically incombination with a conventional pharmaceutical carrier, excipient or thelike. The term “excipient” is used herein to describe any ingredientother than the compound(s) of the invention. Pharmaceutically acceptableexcipients include, but are not limited to, ion exchangers, alumina,aluminum stearate, lecithin, self-emulsifying drug delivery systems(SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate,surfactants used in pharmaceutical dosage forms such as Tweens or othersimilar polymeric delivery matrices, serum proteins, such as human serumalbumin, buffer substances such as phosphates, glycine, sorbic acid,potassium sorbate, partial glyceride mixtures of saturated vegetablefatty acids, water, salts or electrolytes, such as protamine sulfate,disodium hydrogen phosphate, potassium hydrogen phosphate,sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethyl cellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, and wool fat.Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemically modifiedderivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-b-cyclodextrins, or other solubilized derivatives canalso be advantageously used to enhance delivery of compounds of theformulae described herein. Dosage forms or compositions containing acompound as described herein in the range of 0.005% to 100% with thebalance made up from non-toxic carrier may be prepared. The contemplatedcompositions may contain 0.001%-100% active ingredient, in oneembodiment 0.1-95%, in another embodiment 75-85%. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington: The Science andPractice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins. 2005.

In one preferred embodiment, the compositions will take the form of aunit dosage form such as a pill or tablet and thus the composition maycontain, along with the active ingredient, a diluent such as lactose,sucrose, dicalcium phosphate, or the like; a lubricant such as magnesiumstearate or the like; and a binder such as starch, gum acacia,polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or thelike. In another solid dosage form, a powder, marume, solution orsuspension (e.g., in propylene carbonate, vegetable oils ortriglycerides) is encapsulated in a gelatin capsule. Unit dosage formsin which the two active ingredients are physically separated are alsocontemplated; e.g., capsules with granules of each drug; two-layertablets; two-compartment gel caps, etc.

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, etc. an active compound as definedabove and optional pharmaceutical adjuvants in a carrier (e.g., water,saline, aqueous dextrose, glycerol, glycols, ethanol or the like) toform a solution or suspension. If desired, the pharmaceuticalcomposition can also contain minor amounts of nontoxic auxiliarysubstances such as wetting agents, emulsifying agents, solubilizingagents, pH buffering agents and the like (e.g., sodium acetate, sodiumcitrate, cyclodextrine derivatives, sorbitan monolaurate,triethanolamine acetate, triethanolamine oleate, and the like).Injectables can be prepared in conventional forms, either as liquidsolutions or suspensions, as emulsions, or in solid forms suitable fordissolution or suspension in liquid prior to injection. The percentageof active compound contained in such parenteral compositions is highlydependent on the specific nature thereof, as well as the activity of thecompound and the needs of the subject. However, percentages of activeingredient of 0.01% to 10% in solution are employable, and will behigher if the composition is a solid, which will be subsequently dilutedto the above percentages. In some embodiments, the composition willcomprise 0.2-2% of the active agent in solution.

It is to be noted that concentrations and dosage values may also varywith the severity of the condition to be alleviated. It is to be furtherunderstood that for any particular patient, specific dosage regimensshould be adjusted over time according to the individual need and theprofessional judgment of the person administering or supervising theadministration of the compositions, and that the concentration rangesset forth herein are exemplary only and are not intended to limit thescope or practice of the claimed compositions.

Solid compositions can be provided in various different types of dosageforms, depending on the physicochemical properties of the drug, thedesired dissolution rate, cost considerations, and other criteria. Inone of the embodiments, the solid composition is a single unit. Thisimplies that one unit dose of the drug is comprised in a single,physically shaped solid form or article. In other words, the solidcomposition is coherent, which is in contrast to a multiple unit dosageform, in which the units are incoherent.

Examples of single units which may be used as dosage forms for the solidcomposition include tablets, such as compressed tablets, film-likeunits, foil-like units, wafers, lyophilized matrix units, and the like.In a preferred embodiment, the solid composition is a highly porouslyophilized form. Such lyophilizates, sometimes also called wafers orlyophilized tablets, are particularly useful for their rapiddisintegration, which also enables the rapid dissolution of the activecompound.

On the other hand, for some applications the solid composition may alsobe formed as a multiple unit dosage form as defined above. Examples ofmultiple units are powders, granules, microparticles, pellets, beads,lyophilized powders, and the like. In one embodiment, the solidcomposition is a lyophilized powder. Such a dispersed lyophilized systemcomprises a multitude of powder particles, and due to the lyophilizationprocess used in the formation of the powder, each particle has anirregular, porous microstructure through which the powder is capable ofabsorbing water very rapidly, resulting in quick dissolution.

Another type of multiparticulate system which is also capable ofachieving rapid drug dissolution is that of powders, granules, orpellets from water-soluble excipients which are coated with the drug, sothat the drug is located at the outer surface of the individualparticles. In this type of system, the water-soluble low molecularweight excipient is useful for preparing the cores of such coatedparticles, which can be subsequently coated with a coating compositioncomprising the drug and, preferably, one or more additional excipients,such as a binder, a pore former, a saccharide, a sugar alcohol, afilm-forming polymer, a plasticizer, or other excipients used inpharmaceutical coating compositions.

Also provided herein are kits. Typically, a kit includes one or morecompounds or compositions as described herein. In certain embodiments, akit can include one or more delivery systems, e.g., for delivering oradministering a compound as provided above, and directions for use ofthe kit (e.g., instructions for treating a patient). In anotherembodiment, the kit can include a compound or composition as describedherein and a label that indicates that the contents are to beadministered to a patient with cancer. In another embodiment, the kitcan include a compound or composition as described herein and a labelthat indicates that the contents are to be administered to a patientwith one or more of hepatocellular carcinoma, colon cancer, leukemia,lymphoma, sarcoma, ovarian cancer, diabetic retinopathy, neovascularglaucoma, rheumatoid arthritis, psoriasis, mycotic and viral infections,osteochondrodysplasia, Alzheimer's disease, osteoarthritis, polyposiscoli, osteoporosis-pseudoglioma syndrome, familial exudativevitreoretinopathy, retinal angiogenesis, early coronary disease,tetra-amelia syndrome, Müllerian-duct regression and virilization,SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletaldysplasia, focal dermal hypoplasia, autosomal recessive anonychia,neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile Xsyndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome,Beckwith-Wiedemann Syndrome and Rett syndrome.

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

Methods of Treatment

The compounds and compositions provided herein can be used as inhibitorsof one or more members of the Wnt pathway, including one or more Wntproteins, and thus can be used to treat a variety of disorders anddiseases in which aberrant Wnt signaling is implicated, such as cancerand other diseases associated with abnormal angiogenesis, cellularproliferation, and cell cycling. Accordingly, the compounds andcompositions provided herein can be used to treat cancer, to reduce orinhibit angiogenesis, to reduce or inhibit cellular proliferation andcorrect an genetic disorder due to mutations in Wnt signalingcomponents. Non-limiting examples of diseases which can be treated withthe compounds and compositions provided herein include a variety ofcancers, diabetic retinopathy, neovascular glaucoma, rheumatoidarthritis, psoriasis, mycotic and viral infections,osteochondrodysplasia, Alzheimer's disease, osteoarthritis, polyposiscoli, osteoporosis-pseudoglioma syndrome, familial exudativevitreoretinopathy, retinal angiogenesis, early coronary disease,tetra-amelia syndrome, Müllerian-duct regression and virilization,SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletaldysplasia, focal dermal hypoplasia, autosomal recessive anonychia,neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile Xsyndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome,Beckwith-Wiedemann Syndrome and Rett syndrome.

With respect to cancer, the Wnt pathway is known to be constitutivelyactivated in a variety of cancers including, for example, colon cancer,hepatocellular carcinoma, lung cancer, ovarian cancer, prostate cancer,pancreatic cancer and leukemias such as CML, CLL and T-ALL. Theconstitutive activation is due to constitutively active β-catenin,perhaps due to its stabilization by interacting factors or inhibition ofthe degradation pathway. Accordingly, the compounds and compositionsdescribed herein may be used to treat these cancers in which the Wntpathway is constitutively activated. In certain embodiments, the canceris chosen from hepatocellular carcinoma, colon cancer, leukemia,lymphoma, sarcoma and ovarian cancer.

Other cancers can also be treated with the compounds and compositionsdescribed herein.

More particularly, cancers that may be treated by the compound,compositions and methods described herein include, but are not limitedto, the following:

1) Breast cancers, including, for example ER⁺ breast cancer, ER⁻ breastcancer, her2⁻ breast cancer, her2⁺ breast cancer, stromal tumors such asfibroadenomas, phyllodes tumors, and sarcomas, and epithelial tumorssuch as large duct papillomas; carcinomas of the breast including insitu (noninvasive) carcinoma that includes ductal carcinoma in situ(including Paget's disease) and lobular carcinoma in situ, and invasive(infiltrating) carcinoma including, but not limited to, invasive ductalcarcinoma, invasive lobular carcinoma, medullary carcinoma, colloid(mucinous) carcinoma, tubular carcinoma, and invasive papillarycarcinoma; and miscellaneous malignant neoplasms. Further examples ofbreast cancers can include luminal A, luminal B, basal A, basal B, andtriple negative breast cancer, which is estrogen receptor negative(ER⁻), progesterone receptor negative, and her2 negative (her2⁻). Insome embodiments, the breast cancer may have a high risk Oncotype score.

2) Cardiac cancers, including, for example sarcoma, e.g., angiosarcoma,fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma;fibroma; lipoma and teratoma.

3) Lung cancers, including, for example, bronchogenic carcinoma, e.g.,squamous cell, undifferentiated small cell, undifferentiated large cell,and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchialadenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma.

4) Gastrointestinal cancer, including, for example, cancers of theesophagus, e.g., squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, and lymphoma; cancers of the stomach, e.g., carcinoma,lymphoma, and leiomyosarcoma; cancers of the pancreas, e.g., ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,and vipoma; cancers of the small bowel, e.g., adenocarcinoma, lymphoma,carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma,neurofibroma, and fibroma; cancers of the large bowel, e.g.,adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, andleiomyoma.

Genitourinary tract cancers, including, for example, cancers of thekidney, e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma,and leukemia; cancers of the bladder and urethra, e.g., squamous cellcarcinoma, transitional cell carcinoma, and adenocarcinoma; cancers ofthe prostate, e.g., adenocarcinoma, and sarcoma; cancer of the testis,e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, and lipoma.

6) Liver cancers, including, for example, hepatoma, e.g., hepatocellularcarcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma;hepatocellular adenoma; and hemangioma.

7) Bone cancers, including, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochrondroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors.

8) Nervous system cancers, including, for example, cancers of the skull,e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans;cancers of the meninges, e.g., meningioma, meningiosarcoma, andgliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma,glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors;and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma,and sarcoma.

9) Gynecological cancers, including, for example, cancers of the uterus,e.g., endometrial carcinoma; cancers of the cervix, e.g., cervicalcarcinoma, and pre tumor cervical dysplasia; cancers of the ovaries,e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinouscystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumors,Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma;cancers of the vulva, e.g., squamous cell carcinoma, intraepithelialcarcinoma, adenocarcinoma, fibrosarcoma, and melanoma; cancers of thevagina, e.g., clear cell carcinoma, squamous cell carcinoma, botryoidsarcoma, and embryonal rhabdomyosarcoma; and cancers of the fallopiantubes, e.g., carcinoma.

10) Hematologic cancers, including, for example, cancers of the blood,e.g., acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, and myelodysplastic syndrome, Hodgkin'slymphoma, non Hodgkin's lymphoma (malignant lymphoma) and Waldenström'smacroglobulinemia.

11) Skin cancers and skin disorders, including, for example, malignantmelanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi'ssarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma,keloids, and psoriasis.

12) Adrenal gland cancers, including, for example, neuroblastoma.

Cancers may be solid tumors that may or may not be metastatic. Cancersmay also occur, as in leukemia, as a diffuse tissue. Thus, the term“tumor cell,” as provided herein, includes a cell afflicted by any oneof the above identified disorders.

A method of treating cancer using a compound or composition as describedherein may be combined with existing methods of treating cancers, forexample by chemotherapy, irradiation, or surgery (e.g., oophorectomy).In some embodiments, a compound or composition can be administeredbefore, during, or after another anticancer agent or treatment.

The compounds and compositions described herein can be used asanti-angiogenesis agents and as agents for modulating and/or inhibitingthe activity of protein kinases, thus providing treatments for cancerand other diseases associated with cellular proliferation mediated byprotein kinases. For example, the compounds described herein can inhibitthe activity of one or more kinases, such as CDKs, VEGF, CLK, HIPK, Abl,JAK and CHK-1, or cyclin complexes thereof. Accordingly, provided hereinis a method of treating cancer or preventing or reducing angiogenesisthrough kinase inhibition, such as through inhibition of VEGF, CHK-1,CLK, HIPK, Abl, JAK, CDK4 or CDK4/D-type cyclin complexes and/or CDK2 orCDK2/E-type cyclin complexes.

In addition, and including treatment of cancer, the compounds andcompositions described herein can function as cell-cycle control agentsfor treating proliferative disorders in a patient. Disorders associatedwith excessive proliferation include, for example, cancers, psoriasis,immunological disorders involving undesired proliferation of leukocytes,and restenosis and other smooth muscle disorders. Furthermore, suchcompounds may be used to prevent de-differentiation of post-mitotictissue and/or cells.

Diseases or disorders associated with uncontrolled or abnormal cellularproliferation include, but are not limited to, the following:

-   -   a variety of cancers, including, but not limited to, carcinoma,        hematopoietic tumors of lymphoid lineage, hematopoietic tumors        of myeloid lineage, tumors of mesenchymal origin, tumors of the        central and peripheral nervous system and other tumors including        melanoma, seminoma and Kaposi's sarcoma.    -   a disease process which features abnormal cellular        proliferation, e.g., benign prostatic hyperplasia, familial        adenomatosis polyposis, neuro-fibromatosis, atherosclerosis,        pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis,        restenosis following angioplasty or vascular surgery,        hypertrophic scar formation, inflammatory bowel disease,        transplantation rejection, endotoxic shock, and fungal        infections.    -   defective apoptosis-associated conditions, such as cancers        (including but not limited to those types mentioned        hereinabove), viral infections (including but not limited to        herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and        adenovirus), prevention of AIDS development in HIV-infected        individuals, autoimmune diseases (including but not limited to        systemic lupus erythematosus, rheumatoid arthritis, psoriasis,        autoimmune mediated glomerulonephritis, inflammatory bowel        disease and autoimmune diabetes mellitus), neurodegenerative        disorders (including but not limited to Alzheimer's disease,        amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's        disease, AIDS-related dementia, spinal muscular atrophy and        cerebellar degeneration), myelodysplastic syndromes, aplastic        anemia, ischemic injury associated with myocardial infarctions,        stroke and reperfusion injury, arrhythmia, atherosclerosis,        toxin-induced or alcohol related liver diseases, hematological        diseases (including but not limited to chronic anemia and        aplastic anemia), degenerative diseases of the musculoskeletal        system (including but not limited to osteroporosis and        arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis,        multiple sclerosis, kidney diseases and cancer pain.    -   genetic diseases due to mutations in Wnt signaling components,        such as polyposis coli, osteoporosis-pseudoglioma syndrome,        familial exudative vitreoretinopathy, retinal angiogenesis,        early coronary disease, tetra-amelia syndrome, Müllerian-duct        regression and virilization, SERKAL syndrome, diabetes mellitus        type 2, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel        phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity,        split-hand/foot malformation, caudal duplication syndrome, tooth        agenesis, Wilms tumor, skeletal dysplasia, focal dermal        hypoplasia, autosomal recessive anonychia, neural tube defects,        alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF        syndrome, Angelman syndrome, Prader-Willi syndrome,        Beckwith-Wiedemann Syndrome and Rett syndrome.

The compounds and compositions may also be useful in the inhibition ofthe development of invasive cancer, tumor angiogenesis and metastasis.

Moreover, the compounds and compositions, for example, as inhibitors ofthe CDKs, can modulate the level of cellular RNA and DNA synthesis andtherefore are expected to be useful in the treatment of viral infectionssuch as HIV, human papilloma virus, herpes virus, Epstein-Barr virus,adenovirus, Sindbis virus, pox virus and the like.

Compounds and compositions described herein can inhibit the kinaseactivity of, for example, CDK/cyclin complexes, such as those active inthe G₀. or G.₁ stage of the cell cycle, e.g., CDK2, CDK4, and/or CDK6complexes.

Evaluation of Biological Activity

The biological activity of the compounds described herein can be testedusing any suitable assay known to those of skill in the art, e.g., WO2001/053268 or WO 2005/009997. For example, the activity of a compoundmay be tested using one or more of the test methods outlined below.

In one example, tumor cells may be screened for Wnt independent growth.In such a method, tumor cells of interest are contacted with a compound(i.e. inhibitor) of interest, and the proliferation of the cells, e.g.by uptake of tritiated thymidine, is monitored. In some embodiments,tumor cells may be isolated from a candidate patient who has beenscreened for the presence of a cancer that is associated with a mutationin the Wnt signaling pathway. Candidate cancers include, withoutlimitation, those listed above.

In another example, one may utilize in vitro assays for Wnt biologicalactivity, e.g. stabilization of β-catenin and promoting growth of stemcells. Assays for biological activity of Wnt include stabilization ofβ-catenin, which can be measured, for example, by serial dilutions of acandidate inhibitor composition. An exemplary assay for Wnt biologicalactivity contacts a Wnt composition in the presence of a candidateinhibitor with cells, e.g. mouse L cells. The cells are cultured for aperiod of time sufficient to stabilize β-catenin, usually at least about1 hour, and lysed. The cell lysate is resolved by SDS PAGE, thentransferred to nitrocellulose and probed with antibodies specific forβ-catenin.

In a further example, the activity of a candidate compound can bemeasured in a Xenopus secondary axis bioassay (Leyns, L. et al. Cell(1997), 88(6), 747-756).

Example 2

Another screening assay for Wnt activity is described as follows.Reporter cell lines can be generated by stably transducing cells ofcancer cell lines (e.g., colon cancer) with a lentiviral construct thatinclude a wnt-responsive promoter driving expression of the fireflyluciferase gene.

Lentiviral constructs can be made in which the SP5 promoter, a promoterhaving eight TCF/LEF binding sites derived from the SP5 promoter, islinked upstream of the firefly luciferase gene. The lentiviralconstructs can also include a hygromycin resistance gene as a selectablemarker. The SP5 promoter construct can be used to transduce SW480 cells,a colon cancer cell line having a mutated APC gene that generates atruncated APC protein, leading to de-regulated accumulation ofβ-catenin. A control cell line can be generated using another lentiviralconstruct containing the luciferase gene under the control of the SV40promoter which does not require β-catenin for activation.

Cultured SW480 cells bearing a reporter construct can be distributed atapproximately 10,000 cells per well into 384 well multiwell plates.Compounds from a small molecule compound library can then be added tothe wells in half-log dilutions using a three micromolar topconcentration. A series of control wells for each cell type receive onlybuffer and compound solvent. Twenty-four hours after the addition ofcompound, reporter activity for luciferases can be assayed, for example,by addition of the BrightGlo luminescence reagent (Promega) and theVictor3 plate reader (Perkin Elmer). Readings can be normalized to DMSOonly treated cells, and normalized activities can then be used in theIC₅₀ calculations. Table 2 shows the activity of selected indazoleanalogs.

TABLE 2 Compound Wnt inhibition, IC₅₀ 1   >10 μM 2   >10 μM 3   >10 μM 429-50 nM 11    4 nM 12 26-35 nM 15  5.6 nM 16 0.38-1.17 μM   17 32-50 nM18 21-39 nM 19 86-206 nM  20   63 nM 21   29 nM 23 34-64 nM

The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

1. (canceled)
 2. A method of treating a genetic disease caused bymutations in Wnt signaling components, wherein the genetic disease isselected from: polyposis coli, osteoporosis-pseudoglioma syndrome,familial exudative vitreoretinopathy, retinal angiogenesis, earlycoronary disease, tetra-amelia syndrome, Müllerian-duct regression andvirilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmannsyndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletaldysplasia, focal dermal hypoplasia, autosomal recessive anonychia,neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile Xsyndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome,Beckwith-Wiedemann Syndrome and Rett syndrome in a subject, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound of Formula Ia, or a pharmaceutically acceptablesalt thereof:

wherein: R¹, R², R⁴, R⁶, R⁷, R⁸ and R⁹ are independently selected fromthe group consisting of H, C₁₋₉ alkyl, halide, —CF₃, —(C₁₋₉alkyl)_(n)carbocyclylR¹³, —(C₁₋₉ alkyl)_(n)heterocyclylR¹³, —(C₁₋₉alkyl)_(n)arylR¹³, —(C₁₋₉ alkyl)_(n)heteroarylR¹³, —(C₁₋₉alkyl)_(n)OR¹⁰, —(C₁₋₉ alkyl)_(n)SR¹⁰, —(C₁₋₉ alkyl)_(n)S(═O)R¹¹, —(C₁₋₉alkyl)_(n)SO₂R¹⁰, —(C₁₋₉ alkyl)_(n)N(R¹⁰)SO₂R¹⁰, —(C₁₋₉alkyl)_(n)SO₂N(R¹⁰)₂, —(C₁₋ ₉ alkyl)_(n)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)C(=A)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)C(=A)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)C(=A)R¹⁰, —NO₂, —CN, —(C₁₋₉ alkyl)_(n)CO₂R¹⁰, and —(C₁₋₉alkyl)_(n)C(=A)R¹⁰; R³ is selected from the group consisting of—NRS(═O)R¹⁴, —(C₁₋₉ alkyl)R¹⁴, -carbocyclylR¹⁴R¹⁵, -heterocyclylR¹⁴R¹⁵,-arylR¹⁴R¹⁵, and -heteroarylR¹⁴R¹⁵; alternatively, one of each of R¹ andR², R² and R³, R³ and R⁴, R⁶ and R⁷, R⁷ and R⁸ or R⁸ and R⁹ are takentogether to form a ring which is selected from the group consisting ofaryl, heteroaryl,

wherein each bond represented by a dashed and solid line represents abond selected from the group consisting of a single bond and a doublebond; each R¹⁰ is independently selected from the group consisting of H,—C₁₋₉ alkyl, —CF₃, —(C₁₋₉ alkyl)_(n)carbocyclyl, —(C₁₋₉alkyl)_(n)heterocyclyl, —(C₁₋₉ alkyl)_(n)aryl, and —(C₁₋₉alkyl)_(n)heteroaryl; each R¹¹ is independently selected from the groupconsisting of —C₁₋₉ alkyl, —CF₃, —(C₁₋₉ alkyl)_(n)carbocyclyl, —(C₁₋₉alkyl)_(n)heterocyclyl, —(C₁₋₉ alkyl)_(n)aryl, and —(C₁₋₉alkyl)_(n)heteroaryl; each R¹² is independently selected from the groupconsisting of —OR¹⁰ and R¹⁰; each R¹³ is 1-5 substituents each selectedfrom the group consisting of H, C₁₋₉ alkyl, halide, —CF₃, carbocyclyl,heterocyclyl, aryl, heteroaryl, —(C₁₋₉ alkyl)_(n)OR¹⁰, —(C₁₋₉alkyl)_(n)SR¹⁰, —(C₁₋₉ alkyl)_(n)S(═O)R¹¹, —(C₁₋₉ alkyl)_(n)SO₂R¹⁰,—(C₁₋₉ alkyl)_(n)N(R¹⁰)SO₂R¹⁰, —(C₁₋₉ alkyl)_(n)SO₂N(R¹⁰)₂, —(C₁₋ ₉alkyl)_(n)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)C(=A)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)C(=A)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)C(=A)R¹⁰, —NO₂, —CN,—(C₁₋₉ alkyl)_(n)CO₂R¹⁰, and —(C₁₋₉ alkyl)_(n)C(=A)R¹⁰; R¹⁴ is selectedfrom the group consisting of —NR¹⁰C(=A)R¹⁰, —NR¹⁰S(═O)R¹¹, —NR¹⁰SO₂R¹⁰,—NR¹⁰C(═O)N(R¹⁶)₂, —NR¹⁰C(═S)N(R¹⁰)₂, —NR¹⁰C(═NR¹²)N(R¹⁰)₂, —N(R¹⁶)₂,—C(═O)NR¹⁰R¹⁷, —C(═S)N(R¹⁰)₂, —C(═NR¹²)N(R¹⁰)₂, —OC(=A)R¹⁰, —C(=A)R¹⁰,—NR¹⁰C(=A)OR¹⁰, and —OC(=A)NR¹⁰R¹⁰; R¹⁵ is 1-4 substituents eachselected from the group consisting of H, C₁₋₉ alkyl, halide, —CF₃,carbocyclylR¹³, heterocyclylR¹³, arylR¹³, heteroarylR¹³, —(C₁₋₉alkyl)_(n)OR¹⁰, —(C₁₋₉ alkyl)_(n)SR¹⁰, —(C₁₋₉ alkyl)_(n)S(═O)R¹¹, —(C₁₋₉alkyl)_(n)SO₂R¹⁰, —(C₁₋₉ alkyl)_(n)N(R¹⁰)SO₂R¹⁰, —(C₁₋₉alkyl)_(n)SO₂N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)C(=A)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)C(=A)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)C(=A)R¹⁰, —NO₂, —CN, —(C₁₋₉ alkyl)_(n)CO₂R¹⁰, and —(C₁₋₉alkyl)_(n)C(=A)R¹⁰; R¹⁶ is —C₁₋₉ alkyl; each R¹⁷ is independentlyselected from the group consisting of -heterocyclylR¹³, —(C₁₋₉alkyl)heterocyclylR¹³, and —(C₁₋₉ alkyl)carbocyclylR¹³; R¹⁸ and R¹⁹ areindependently selected from the group consisting of H, C₁₋₉ alkyl,halide, —(C₁₋₉ alkyl)_(n)carbocyclylR¹³, —(C₁₋₉alkyl)_(n)heterocyclylR¹³, —(C₁₋₉ alkyl)_(n)arylR¹³, —(C₁₋₉alkyl)_(n)heteroarylR¹³, —(C₁₋₉ alkyl)_(n)OR¹⁰, —(C₁₋₉ alkyl)_(n)SR¹⁰,—(C₁₋₉ alkyl)_(n)S(═O)R¹⁰, —(C₁₋₉ alkyl)_(n)SO₂R¹⁰, —(C₁₋₉alkyl)_(n)N(R¹⁰)SO₂R¹⁰, —(C₁₋₉ alkyl)_(n)SO₂N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)C(=A)N(R¹⁰)₂, —(C₁₋₉alkyl)_(n)C(=A)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)C(=A)R¹⁰, —NO₂, —CN,—(C₁₋₉ alkyl)_(n)CO₂R¹⁰, and —(C₁₋₉ alkyl)_(n)C(=A)R¹⁰; alternatively,R¹⁸ and R¹⁹ are taken together to form a ring which is selected from thegroup consisting of benzene and pyridine; each A is independentlyselected from O, S, and NR¹²; Y¹, Y², and Y⁴ are C; Y³ is nitrogen andR⁸ is absent; and each n is 0 or
 1. 3. The method of claim 2, whereinR¹, R² and R⁴ are H and R³ is independently selected from the groupconsisting of —NRS(═O)R¹⁴, —(C₁₋₉alkyl)R¹⁴, -carbocyclylR¹⁴R¹⁵,-heterocyclylR¹⁴R¹⁵, -arylR¹⁴R¹⁵ and -heteroarylR¹⁴R¹⁵.
 4. The method ofclaim 3, wherein R³ is -heterocyclylR¹⁴R¹⁵.
 5. The method of claim 3,wherein R³ is -arylR¹⁴R¹⁵.
 6. The method of claim 3, wherein R³ is-heteroarylR¹⁴R¹⁵.
 7. The method of claim 6, wherein R¹⁴ is—NR¹⁰C(=A)R¹⁰ and A is O.
 8. The method of claim 6, in which theheteroaryl is a pyridine.
 9. The method of claim 8, in which R¹⁴ is—NHC(═O)R¹⁰ and R¹⁰ is selected from the group consisting of —C₁₋₉alkyl, carbocyclyl, aryl and —(C₁₋₉ alkyl)aryl.
 10. The method of claim7, in which R¹⁴ is —C(═O)NHR¹⁷, R¹⁷ is —(C₁₋₉alkyl)carbocyclylR¹³ andR¹³ is H.
 11. The method of claim 2, wherein R⁶ is —(C₁₋₉alkyl)_(n)heteroarylR¹³, n is 0 and R¹³ is H.
 12. The method of claim 2,wherein R¹, R², R⁴, R⁷, and R⁹ are H; R³ is heteroarylR¹⁴R¹⁵; and R⁶ is—(C₁₋₉ alkyl)_(n)arylR¹³.
 13. The method of claim 12, in which R¹⁴ is—NHC(═O)R¹⁰ and R¹⁰ is selected from the group consisting of —C₁₋₉alkyl, carbocyclyl, aryl and —(C₁₋₉ alkyl)aryl.
 14. The method of claim13, wherein R¹³ is fluoro.
 15. The method of claim 2, wherein thegenetic disease is diabetes mellitus type
 2. 16. The method of claim 2,wherein the genetic disease is obesity.
 17. The method of claim 2,wherein the genetic disease is familial exudative vitreoretinopathy. 18.The method of claim 2, wherein the genetic disease is retinalangiogenesis.
 19. The method of claim 2, wherein the genetic disease isneural tube defects.
 20. The method of claim 2, wherein the subject is ahuman.
 21. The method of claim 2, wherein the compound of Formula Ia isselected from the group consisting of:

or a pharmaceutically acceptable salt thereof.